PROFORMA FOR SUBMISSION OF RESEARCH ...dbtepromis.gov.in/Documents/TechnicalDetails/ProposalID...State: Karnataka 3. Status of the Institute: Private Non-Profit Institute Recognized

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PROFORMA FOR SUBMISSION OF RESEARCH & DEVELOPMENT

PROJECTS UNDER BIOINFORMATICS

PART I: GENERAL INFORMATION

1. Name of the Institute/University/Organization submitting the Project Proposal:

Institute of Bioinformatics,

Unit 1, Discoverer building, 7th

Floor,

International Tech Park Bangalore

Whitefield, Bangalore - 560 066

Ph: +91 80 28416140; Fax: +91 80 28416132

Web: www.ibioinformatics.org

2. State: Karnataka

3. Status of the Institute: Private Non-Profit Institute Recognized by DSIR in 2004

4. Name and designation of the Executive Authority of the Institute/University

forwarding the application: Dr. Akhilesh Pandey

Founder and Director

Institute of Bioinformatics

Unit 1, Discoverer building, 7th

Floor,

International Tech Park Bangalore

Whitefield Road, Bangalore - 560 066

Ph: +91 80 28416140; Fax: +91 80 28416132

Email: [email protected]

5. Project Title: “Development of 1000 Human Signaling Pathway Reference Maps- A

Unique 10 Centre Collaborative Network Initiative for Human Resource Development in

Bioinformatics in India”

6. Category of the Project: R&D in Bioinformatics

7. Specific Area: Database Development

8. Duration: 4 Years

9. Total Cost (Rs.): 849.26 lakhs

10. Is the project Single Institutional or Multiple-Institutional S/M)? : M

11. If the project is multi-institutional, please furnish the following:

Project Coordinators

1) Name: Dr. Akhilesh Pandey 2) Name: Dr. Rajesh Raju

Affiliation: Institute of Bioinformatics Affiliation: Institute of Bioinformatics

Address: Discoverer building, 7th Floor, Address: Discoverer building, 7

th Floor,

International Tech Park Bangalore, International Tech Park Bangalore,

Whitefield Road, Bangalore - 560 066, Whitefield Road, Bangalore - 560 066,

Ph: +91 80 28416140; Ph: +91 80 28416140;

Fax: +91 80 28416132 Fax: +91 80 28416132

Email: [email protected] Email: [email protected]

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12. Project Summary (Not to exceed two pages) Cell signaling pathways encompass the topological network of molecular reactions which mediate response to the diverse array of signals that the cells encounter. It is established that dysregulation of signaling pathways is the cornerstone to several diseases such as cancer, diabetes, or neurological disorders. With a large number of genomes being analyzed, it is now clear that an understanding of signaling pathways hold the key to develop strategies to combat these disorders and not merely a listing of mutations and mutated genes. In fact, signaling pathways and not individual genes have already been proposed as therapeutic targets in a number of cancers including breast (Rosen et al., 2010), pancreatic (Xia et al., 2011), non-small-cell lung (Schmid et al., 2010), head and neck (Freudlsperger et al., 2010) and ovarian (Shao et al., 2012) cancers. Thus, analysis of signaling pathways is not only indispensible for understanding biological systems but is also essential to re-establish pathways that have become deregulated in disease states. Out of nearly 4000 genes that encode transmembrane proteins (Lander et al., 2001), only partial information on signaling pathways initiated by less than 200 receptors are available in different pathway resources. Many of these resources are also moving away from its open-source/free-software roots to a user-pay system. Moreover, these resources also lack the pathway information to the level of the genes which are regulated by specific signaling pathways along with their transcriptional regulators. Currently, there is no database available in the public domain that is equipped to address complex biological problems through systems biology approaches. Thus, there is an urgent need for development of a resource of signaling pathways suitable for all systems biology approaches that can be used by the entire spectrum of biomedical community. Towards this, with internal funding, Institute of Bioinformatics, Bangalore, have established a publicly-available freely-accessible resource of human signaling pathways named NetPath (www.netpath.org) (Kandasamy and Mohan et al., Genome Biology, 2010). We have already developed the tool, 'PathBuilder', to streamline pathway development (Kandasamy et al., Bioinformatics, 2010). For the first time in India, we have already initiated post-graduate student training programme in 10 universities, integrating well into curriculum, to develop signaling pathways. Thus far, this revolutionizing effort has led to training of over 200 students from bioinformatics, biochemistry and biotechnology disciplines in these universities. This has already led to the publication of 28 signaling pathways authored by 60 scientists including students and faculty members from several national Universities, research scientists from IOB, and national and international experts of specific signaling pathways. Signaling pathways developed include TGF-beta (Raju et al., Database, 2011); Prolactin signaling pathway (Radhakrishnan et al., Journal of Cell Communication and Signaling, 2012); TWEAK signaling pathway (Bhattacharjee et al., Journal of Signal Transduction, 2012); TSH pathway (Goel et al., Journal of Proteomics and Bioinformatics, 2011); FSH pathway (Telikicherla et al., BMC Research Notes, 2011); Leptin signaling pathway (Nanjappa et al., Journal of Proteomics and Bioinformatics, 2011) and RANKL signaling pathway (Raju et al., Database, 2011). Our community participation effort has already shown lot of promise as an effective and fast-track mode of human resource development in India. We have a larger vision of characterizing most of the signaling pathways in humans. The prime goal of this project is to develop 1000 signaling pathway maps with a panel of national and international experts on specific signaling pathways on board. Simultaneously, we propose to achieve human resource development in this area of biomedical science, by forging a network of Universities to impart training to the post-graduate students of biological sciences in India. To best impart this human resource development programme, we will also facilitate interaction between the students and the faculty members with the world leaders who have significantly contributed to the field of signal transduction through conferences and workshops. The coordinated outcome of this proposed project would transform NetPath into, the largest

open-source repository of human signaling pathways, well-equipped to meet the challenges

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of functional genomics and systems biology. The current data in NetPath is being used for

analysis of experimental data in the context of specific pathways, function and diseases by

the entire biomedical community. A detailed characterization of molecules and their reactions

that synchronize cellular function would accelerate research and enable identification and

attribution of function to a large number of molecules in specific pathways. High-quality

data emanating from this project will be used to develop open-source pathway data

analysis suites and also for developing heuristic methods for the prediction of novel

molecules and their relationships in signaling pathways. Such novel molecules unique to

specific cellular processes may be selectively validated for their therapeutic applications. We are confident that our 1000 signaling pathway reference map will become a worldwide

community standard even before the project is completed. The proposed model of human

resource development in this project will help envision, strengthen and reinforce

biomedical research in India. This will be a continued endeavor with involvement of

bioinformaticians and experimental biologists in India in the subsequent phases to achieve

our goals (Figure 1).

Figure 1: An outline of our goals that will be initiated with this proposal

Over 1000 students from bioscience disciplines will be trained in the period of 4 years under

this project. We are sure that the trained manpower will radiate their knowledge across

various laboratories and institutions in the future. The network and association developed

between premier educational and research organizations in India would enable technology

transfer and interventions channelizing targeted and broader scientific endeavors in the

future. Successful outcome of our vision would place India in the forefront of biomedical

research in the world.

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PART II: PARTICULARS OF INVESTIGATORS

Principal Investigator

13. Name: Dr. T. S. Keshava Prasad

Date of Birth: 08 April, 1975 Sex (M/F): M

Indicate whether Principal Investigator/Co-Investigator: Principal Investigator

Designation: Faculty Scientist

Department: Bioinformatics

Institute/University: Institute of Bioinformatics

Address: Unit 1, Discoverer building, 7th Floor,

International Tech Park Bangalore,

Whitefield, Bangalore – 560 066, Karnataka

Ph: +91 80 28416140; Fax: +91 80 28416132



No. of projects being handled at present: 05

Note: Use separate page, if more investigators are involved..

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Co-investigators from Institute of Bioinformatics

1. Name: Dr. Rajesh Raju

Date of Birth: 05 February, 1981 Sex (M/F): M

Indicate whether Principal Investigator/Co-Investigator: Co-investigator






Whitefield, Bangalore – 560 066, Karnataka.

Ph: +91 80 28416140; Fax: +91 80 28416132



Number of research projects being handled at present: 0

2. Name: Dr. Aditi Chatterjee

Date of Birth: 13 September, 1971 Sex (M/F): F

Indicate whether Principal Investigator/Co-Investigator: Co- investigator


Institute/University: Institute of Bioinformatics, Bangalore



Whitefield Road, Bangalore-560 066, Karnataka.

Ph: +91 80 28416140; Fax: +91 80 28416132



3. Name: Dr. Sowmya Soman

Date of Birth: 17 March, 1981 Sex (M/F): F








Ph: +91 80 28416140; Fax: +91 80 28416132




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4. Name: Dr. Akhilesh Pandey

Date of Birth: 26 August, 1969 Sex (M/F): M


Designation: Founder and Director






Ph: +91 80 28416140; Fax: +91 80 28416132




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Co-investigators and Project Leaders from Participating Research Centers

Project Leaders from Pune University

Name: Dr. Kulkarni-Kale Urmila

Date of Birth: 09 May, 1964 Sex (M/F): F


Designation: Information scientist

Department: Department of Bioinformatics

Institute/University: University of Pune

Address: University of Pune,

Ganeshkhind Road,

Pune - 411 007, Maharashtra.

Ph: +91 20 25692039, 25690195; Fax: +91 20 25690087


Name: Dr. Sangeeta Sawat

Date of Birth: 28 February, 1966 Sex (M/F): F


Designation: Assistant Professor




Ganeshkhind Road,


Ph: +91 20 25692039, 25690195; Fax: +91 20 25690087


Name: Dr. Dattatraya V. Desai

Date of Birth: 31 October, 1974 Sex (M/F): M


Designation: Information scientist




Ganeshkhind Road,


Ph: +91 20 25692039, 25690195; Fax: +91 20 25690087


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Project Leaders from Madurai Kamaraj University

Name: Dr. P. Gunasekaran

Date of Birth: 02 July, 1954 Sex (M/F): M


Designation: Coordinator (NRCBS program and Genomics program),

Senior Professor and Head

Department: Department of Genetics

Institute/University: Madurai Kamaraj University

Address: Center for Excellence in Genomic Sciences,

School of Biological Sciences, Madurai Kamaraj University,

Madurai 625 021, Tamil Nadu.

Ph: +91 452 2458478/2458209/2459873


Name: Dr. S. Krishnaswamy



Designation: Senior Professor, Head & Chairperson

Department: Department of Genetic Engineering


Address: School of Biotechnology,

Madurai Kamaraj University,


Ph: +91 452 2459141


Name: Dr. G. Kumaresan

Date of Birth: 28 June, 1976 Sex (M/F): M


Designation: Associate Professor

Department: Department of Genetics


Address: Center for Excellence in Genomic Sciences,

School of Biological Sciences, Madurai Kamaraj University,


Ph: +91 452 2458478/2458209/2459873


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Project Leaders from Pondicherry University

Name: Dr. Archana Pan

Date of Birth: 06 October, 1966 Sex (M/F): F



Department: Centre for Bioinformatics

Institute/University: Pondicherry University

Address: Pondicherry University,

R.V. Nagar, Kalapet, Puducherry- 605 014.

Ph: +91 413 2655584, 2654419; Fax No: +91 413 2655211, 2655265


Name: Dr. P. P. Mathur



Designation: Professor and Head

Department: Centre for Bioinformatics

Institute/University: Pondicherry University

Address: Pondicherry University,

R.V. Nagar, Kalapet, Puducherry- 605 014.

Ph: +91 413 2655212, 2654419


Project Leaders from Anna University

Name: Dr. P. Gautam

Date of Birth: 22 May, 1959 Sex (M/F): M


Designation: Professor and Chairman, Faculty of Technology

Department: Centre for Biotechnology

Institute/University: Anna University

Address: Centre for Biotechnology,

Anna University, Chennai 600 025, Tamil Nadu.

Ph: +91-44-2235 8371, +91-9444179685


Project Leaders from Armed Forces Medical College

Name: Gp Capt S Shankar M.D.



Designation: Professor

Department: Internal Medicine

Institute/University: Armed Forces Medical College

Address: Department of internal medicine

Armed Forces Medical College,

Wanowrie, Pune – 411 040, Maharashtra.

Ph: +91 9373466044


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Name: Brig Velu Nair, AVSM, VSM**

Date of Birth: 04 May, 1956 Sex (M/F): M



Department: Internal Medicine

Institute/University: Armed Forces Medical College

Address: Department of internal medicine

Armed Forces Medical College,

Wanowrie, Pune – 411 040, Maharashtra.

Ph: 020-2602601 (O)


Project Leaders from University of Kerala

Name: Dr. Achuth Shankar



Designation: Professor and Director (SIUCEB)

Department: Centre of Bioinformatics

Institute/University: University of Kerala

Address: Dept. of Computational Biology & Bioinformatics

State Inter-University Centre of Excellence in Bioinformatics (SIUCEB)

North Campus – Kariavattom, University of Kerala

Thiruvananthapuram- 695581, Kerala.

Ph:+91 471 2308759


Project Leaders from University of Mysore

Name: Dr. H. S. Prakash

Date of Birth: 05 February, 1956 Sex (M/F): M


Designation: Professor

Department: Applied Botany and Biotechnology

Institute/University: University of Mysore

Address: Department of Applied Botany and Biotechnology

Manasagangotri, Mysore-570006, Karnataka.

Ph: +91-821-2419877


Name: Dr. Geetha N. Prashanth

Date of Birth: 18 January, 1972 Sex (M/F): F


Designation: Lecturer





Ph: +91-821-2419825


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Name: Dr. K. Ramachandra Kini



Designation: Reader





Ph: +91-821-2419805 /+91-9448128916


Project Leaders from Mangalore University

Name: Dr. K. K. Vijayalaxmi

Date of Birth: 20 July, 1954 Sex (M/F): F


Designation: Professor and Head of the Department

Department: Applied Zoology

Institute/University: Mangalore University

Address: Department of Applied Zoology,

Mangalore University, Mangalagangotri - 574 199, Karnataka.

Ph: +91-824-2287373


Name: Dr. K. Bhaskar Shenoy

Date of Birth: 10 December, 1960 Sex (M/F): M



Department: Applied Zoology




Ph: +91-824-2287373, +91-824-2284750


Name: Dr. Prashantha Naik




Department: Biosciences




Ph: +91-824-2287261


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Project Leaders from Kuvempu University

Name: Dr. Riaz Mahmood




Department: Post-Graduate Studies and Reseach in Biotechnology

Institute/University: Kuvempu University

Address: Department of Post-Graduate Studies and Reseach in Biotechnology

Bioscience Block, Kuvempu University, Jnanasahyadri

Shankaraghatta-577 451, Karnataka.

Phone: +91-8282-256235, 256167 Fax: 08282-256255


Name: H. S. Santosh Kumar




Department: Post-Graduate Studies and Reseach in Biotechnology

Institute/University: Kuvempu University

Address: Department of Post-Graduate Studies and Reseach in Biotechnology

Bioscience Block, Kuvempu University, Jnanasahyadri

Shankaraghatta-577 451, Karnataka.

Phone: +91-8282-256235, 256167 Fax: 08282-256255


Project Leaders from Central University Kerala

Name: Dr. Sameer Kumar

Date of Birth: 14 August, 1980 Sex (M/F): M



Department: Biochemistry and Molecular Biology

Institute/University: Central University of Kerala, Kasargod

Address: Dept of Biochemistry and Molecular Biology

Central University of Kerala,

Padennakkad (P.O), Nileshwar,

Kasaragod-671 328, Kerala.

Ph: +91-9447697893


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PART III: TECHNICAL DETAILS OF PROJECT

16. Introduction

16.1 Origin of the proposal

Despite a decade after the first draft of human genome became available, elucidation of the

role of proteins and the effect of large number of sequence variations on the phenotype still

persists to be a huge challenge to the scientific community. This is largely due to the fact that

multiple gene products can arise from a single gene and that their expression could be

temporally regulated in cells/cell types at their different stages of growth and development.

Besides, post-translational modifications are one of the major determinants of localization

and regulation of activity of proteins, and hence their function. It has now become clear that

proteins exist in larger dynamic complexes forming networks and that spatiotemporal flux in

these complex networks drive cellular processes. In biological systems, cellular processes are

coordinatively regulated through autocrine, paracrine, endocrine and juxtacrine signals. The

flux in networks which mediates transduction of signals through their specific receptors to

bring about cellular response is known as signaling pathways. Thus, signaling pathways

essentially integrate functional genomics to systems biology.

The advances in genomics, transcriptomics and proteomics technology platforms have

enabled large-scale identification and quantification of transcripts, proteins and protein-

protein interactions with high sensitivity and specificity. These technology platforms have

also facilitated the identification of genes (both at the level of mRNA or protein) that are

differentially regulated in diverse disease conditions such as cancer, arthritis, or neurological

disorders. In recent years, the biomedical research community has also realized the

importance and promoted the development of resources that manually or computationally

catalog biological information such as protein-protein interactions and gene expression. Even

though many software have been developed that adds various analysis components to these

interaction or expression data sets, in most cases, they do not provide an accurate biological

premise for these data. This lack of biological premise is the result of high heterogeneity

in the experimental data, context-specificity, spatiotemporal regulation of protein

activity, post-translational modifications of proteins and the ability of proteins to

interact with multiple proteins.

Biological pathways are a well co-ordinated and regulated set of molecular events which

includes protein-protein interactions, post-translational modifications, intracellular movement

of proteins and gene expression which brings about a particular phenotypic effect in the cell.

Although a large number of proteins and their sequence variations had been associated

with diverse diseases, their participating signal transduction pathways have long been

considered as the most effective targets for therapy. At the human interface, these

pathways are elicited when the cells are subjected to diverse array of extracellular or

intracellular stimuli. These signaling pathways provide important modular framework for

studying the biological context of a set of molecular interactions or a gene/protein expression

dataset. Molecular reactions that takes place under a particular stimulus is scattered across the

literature. There have been, in the past, efforts towards the generation of pathway resources.

However, many of these efforts are not comprehensive in their coverage of molecules and

predominantly consider only components of canonical modules. Moreover, many of them do

not provide the data in community standard data exchange formats including PSI-MI,

BioPAX and SBML so that it can be used with various pathway analysis software. Hence,

generation of resources which put molecular reactions in a pathway perspective that

can be used by the entire scientific community for systems biology approaches is the

need of the hour.

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Initial effort- NetPath

Institute of Bioinformatics (IOB) has initiated the development of resource of signaling

pathways to study the relationship among proteins that mediate cellular responses. In

collaboration with the Computational Biology Center at Memorial Sloan-Kettering Cancer

Center and with Gary Bader's lab at the University of Toronto, IOB has developed a set of 10

cancer signaling pathways for 'Cancer Cell Map' (http://cancer.cellmap.org/cellmap/)

(Unpublished) (Figure 2).

Scientists at IOB have improved this initial effort (with internal funding) to develop another

set of ten human signaling pathways pertaining to immune system which includes B cell

receptor, T cell receptor, Interleukins- 1, 2, 3, 4, 5, 6, 7 and 9 pathways. Each of these

signaling pathways were reviewed and approved by experts who represented 18 international

research centres. This has led to the development of a unique resource of open access human

signaling pathways named 'NetPath' (http://www.netpath.org/). NetPath, published in

‘Genome Biology’, was one of

the most highly accessed

research articles in 2010

(Kandasamy and Mohan et al.,

2010) (Figure 3). NetPath

currently hosts 27 ligand-

receptor specific human

signaling pathways of utmost

relevance to cancer, immunity,

obesity and endocrine system,

freely accessible to the

biomedical community (Figure

4). A pathway in NetPath

contains spatiotemporal

biochemical reactions induced

by the interaction of specific

Figure 2: A screenshot of the home page of Cancer Cell Map

Figure 3: NetPath was one of the most highly assessed

articles published in Genome Biology

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ligand(s) to their receptor(s) identified from published research articles. These reactions are

characterized into protein-protein interactions, enzyme-substrate and post-translational

modification events, and protein transport events across various cellular compartments.

Along with transcriptional regulators, NetPath also documents genes transcriptionally

regulated by specific pathways.

Figure 4: A screenshot of the home page of NetPath- NetPath home page has options for

browsing the pathways and search for the molecules. It also contains the statistics on the

number of pathways and reactions available in NetPath.

Pathways in NetPath have more than ten times the amount of data than any other resource

currently available in the public domain including KEGG (Kanehisa et al., 1996, Kanehisa et

al., 2004) (moving away from its open-source/free-software roots to a user-pay system),

NCI-PID (Carl et al., 2009), BioCarta (http://www.biocarta.com/index.asp) and Reactome

(Croft et al., 2011). Taking into account the comprehensiveness, heterogeneity and

complexity, for graphical representation of NetPath data, scientists at IOB have also

developed signaling pathway maps named 'NetSlim' (Raju et al., 2011). NetSlim contains

high-confidence pathway maps generated by applying a set of confidence criteria to

individual NetPath pathway reactions. NetPath and NetSlim pathway data are available for

download in standard formats such as PSI-MI version 2.5 (Hermjakob et al., 2004), BioPAX

level 3 (Demir et al., 2010) and SBML version 2.1 (Hucka et al., 2003), while the NetSlim

pathway maps are available for download in GPML (Van Iersel et al., 2008), GenMAPP

(Salomonis et al., 2007), JPEG and PDF formats from NetSlim and WikiPathways (Pico et

al., 2008 and Kelder et al., 2012) under adaptive Creative Commons License. NetSlim model

of TGF-beta pathway in NetPath is shown in Figure 5 as a prototype.

NetPath and NetSlim data in standard formats are also available through

WikiPathways and Cancer Cellmap (http://cancer.cellmap.org/cellmap/). NetPath and

NetSlim data in these standard formats also available through WikiPathways and Cancer

Cellmap (http://cancer.cellmap.org/cellmap/).

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Figure 5: The TGF-beta NetSlim map developed using PathVisio- The nodes and edges

represent the molecules and their reactions, respectively. A key for the various symbols,

colors and abbreviations used in the pathway diagram is provided in NetSlim database

(www.netpath.org/netslim).

TGF-beta Signaling Pathway

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These incorporated into NCBI BioSystems (Geer et al., 2010), and BioGPS (Wu et al., 2009)

have been invariably used by various pathway analysis tools such as Gene Spring, Cytoscape

(Shannon et al., 2003), and Integrated Pathway Resources, Analysis and Visualization

System (iPAVS) (Sreenivasaiah et al., 2012) for data analysis. Current pathway analysis

suites integrate data from various resources in the public domain which lack consensus

among them. These commercial suites uses anonymous data (data undefined) that

generate confusion among the users on the source, connectivity of molecules, and the

quality of the results.

We have already established the resources such as Human Protein Reference Database

(HPRD) (Goel et al.,, 2012, Goel et al., 2010, Prasad et al., 2009, Mishra et al., 2006, Peri et

al., 2004, Peri et al, 2003) (cited by over 1000 research articles including those in Nature,

Science and Cell), Human Proteinpedia (Kandasamy et al., 2009, Mathivanan et al., 2008)

(published in Nature Biotechnology), Plasma Proteome Database (Muthusamy et al., 2005)

and Resource for Asian Primary Immunodeficiency Diseases (RAPID) (Keerthikumar et al.,

2009) (published in Nucleic Acids Research) as gold-standard databases for human proteome

information. To the best of our knowledge, data from HPRD, Human Proteinpedia and

RAPID databases from India that have been linked into NCBI databases such as Entrez

Gene and RefSeq.

NetPath pathways are the most used and visited pathways in WikiPathways

(www.wikipathways.org) compared to the pathways provided by others. The public

availability of NetPath and NetSlim data have enabled researchers worldwide to

analyze and represent transcriptomics and proteomics data derived from various high-

throughput experimental platforms (Ritchie et al., 2012; Jiao et al., 2011; Navab et al.,

2011; Milenković et al., 2011; Morris et al., 2011; Turner et al., 2011; Grady et al., 2011;

Yamamoto et al., 2011; Kelder et al., 2011; Yaspan and Veatch, 2011; Astsaturov et al.,

2010; Gu et al., 2010; Imamura et al., 2010; Hammond et al., 2010; Isserlin et al., 2010;

Mostaghel et al., 2010; Hoang et al., 2010; Chaussepied et al., 2010; Wasiliew et al., 2009;

Bush et al., 2009; Bouwens et al., 2009; Rutella et al., 2009; van Iersel et al., 2008; and Oler

et al., 2008).

We have also embarked upon a new social initiative wherein we trained masters’ level

students from universities and involved them in the development of signaling pathways. With

the success of this pilot social experiment, we aim to take this initiative to the next level to

generate a layer of competent students who can spread the current concepts in signal

transduction across the bioscience students’ community in India.

In parallel, considering the utmost utility and necessity to put together pathway information

required to analyze complex biological experimental data, we propose to expand the number

of pathways in NetPath to 1000 signaling pathways. Looking forward to this, we have

initially set out to develop specific pathways of clinical significance that are not provided by

other resources in the public domain. We have revolutionised the development of signaling

pathways by training post-graduate level students from different universities in India. An early exposure to the details of signal transduction has already gained many of them

employment and Ph.D. positions within and across India. There are over 100 human signaling

pathways currently under development at IOB. The current status of the signaling pathways

being developed by the participation of post-graduate students from the current participating

institutes and others is provided in Table 1.

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Participating

Institutes Project Leaders Signaling pathways Status

Pondicherry

University

Dr. Archana Pan

and

Dr. P. P. Mathur

(Centre for

Bioinformatics)

Thyroid Stimulating hormone Goel et al., Journal of Proteomics and

Bioinformatics, 2011

TNF-related weak inducer of apoptosis Bhattacharjee et al., Journal of Signal

Transduction, 2011

Growth Hormone Releasing Hormone Under Review

Parathyroid hormone Under Review

Thrombin Under Review

TNF-related apoptosis-inducing ligand Under Review

Erythropoietin Under Review

Glucagon Under Review

University of

Mysore

Dr. H. S. Prakash,

Dr. Geetha N. P. and Dr. K. R. Kini

(Applied Botany and

Biotechnology)

Fibroblast growth factor Under Review

Hepatocyte growth factor Under Review

Nerve growth factor Under Review

Thrombopoietin Under Review

University of

Pune

Dr. Urmila Kale,

Dr. Sangeetha Sawat

and Dattatraya V.

Desai (Bioinformatics

centre)

Prolactin Radhakrishnan et al, Journal of cell

communication and signaling, 2012

Interleukin-11 Under Review

Platelet Activating Factor Under Review

Armed Forces

Medical

College

Dr. Shankar S

and

Dr. Velu Nair (Haematology)

Corticotropin Releasing Hormone Under Review

fms-like tyrosine kinase receptor-3 Under Review

Melatonin Under Review

Oncostatin-M Under Review

Neurotensin Under Review

Kuvempu

University

Dr. Riaz Mahmood

and

H. S. Santosh

(Department of Post-

Graduate Studies and

Research in

Biotechnology and

Bioinformatics)

RANKL/RANK Raju et al., Database, 2011

Anexelekto (AXL) Under Review

FAS Under Review

Anti-mullerian hormone Under Review

Dr. MGR

University

Dr. Rama

Vaidyanathan

and

Dr. N. Sudhakar (Biotechnology)

Tie2/TEK Under Review

Ghrelin Under Review

Amrita

University

Dr. Bipin Nair

(Amrita School of

Biotechnology)

Leptin Nanjappa et al., Journal of

Proteomics and Bioinformatics, 2011

National

Institute for

Research in

Reproductive

Health

Dr. Srabani

Mukherjee

(Molecular

Endocrinology)

Follicle Stimulating Hormone Telikicherla et al., BMC Research

Notes, 2011

Table: 1 Current status of signaling pathways under development at IOB

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This effort has also led to the unique opportunity for publication by students at their post-

graduate level (Figure 6).

Figure 6: A screenshot of a set of specific signaling pathways published by scientists at

Institute of Bioinformatics in international peer-reviewed journals with the students,

the faculty members and the pathway authorities as co-authors.

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Integrating experimental data on molecules obtained at the level of DNA, RNA and protein

level encompasses almost all aspects of biology. The evolving technological platforms are

not being handled by students during their coursework practical sessions. Thus, training post-

graduate level students from various universities in India on the development of signaling

pathways would foster human resource development. Our social experiment has gained

broad attention and appreciation in the university bioscience community in India. This

human resource development programme in the current participating institutes and

prospectively new institutes across the country would also potentiate the development of

1000 signaling pathways for NetPath

These pathways were developed by the participation of students from currently Participating

Institutes. The students and the Project leaders from the respective Participating Centres are

authors in these publications.

Integrating protein-protein interactions, PTMs, activation/inhibition status of proteins with

reference to specific assays, spatial distribution of proteins across various subcellular

compartments coupled to transcriptional regulation of genes by specific signaling pathways,

NetPath will serve as a unique platform for heuristic approaches to global pathway analysis.

The pathway data obtained in this proposed project would form the basis for computational

analysis of data pertaining to transient behaviour of cells coupled to their biological processes

and also to devise new hypothesis driven experimental approaches in the subsequent phases

of our study. With very competent bioinformaticians in India in different universities and

research institutes, we plan to carry forward this community participation and human

resource development programme to develop open-access pathway analysis software suites in

the next phase of our research. Thus, our three-tier approach- (i) development of a

comprehensive resource of signaling pathways, (ii) development of open-access pathway

analysis suites and (iii) validation, and hypothesis- driven experimental approaches to

identify novel molecules and missing links in signaling pathways would help place India

in forefront of biomedical research.

21

16.2 Definition of the problem

Physiologically, cells encounter various ligands and their coordinated outcomes are difficult

to be exactly replicated ex vivo. Such a scenario has necessitated reductionist approaches to

study and characterize biochemical events mediating response to individual ligands through

multiple receptors and vice versa. The initial human genome sequence project estimated 20%

of the genes (over 4000 genes) to code for membrane proteins (Lander et al., 2001). Based on

the signaling mechanism, cell surface receptors are mainly classified into receptor tyrosine

kinases (Robinson et al., 2000), receptor serine/ threonine kinases (Ten Dijke et al., 1994), G-

Protein coupled receptors (Harmar et al., 2009), guanylyl cyclase receptors, ionotropic

receptors (Collingridge et al., 2009) and others which depend on cytoplasmic kinases or

adaptor molecules for signal transduction. Of many intracellular receptors, nuclear receptors

form a category of bifunctional receptors which binds to their membrane-permeable ligands

and are capable of regulating expression of their target genes by directly binding to specific

responsive elements.

The reactions pertaining to signaling pathways scattered in literature can also be

characterized into those derived from experiments involving activation of (i) a specific

receptor by multiple ligands, (ii) a specific ligand-receptor combination, and (iii) multiple

receptors by a specific ligand. Thus, the identification of pathway specific reactions under

these categories to devise topology of reactions in the pathways inevitably requires human

intrusion. Classical pathway representations are not sufficient to meet the challenges of

integrating heterogeneous datasets to obtain deeper insights into signal processing and

transduction. Thus, there is an increasing need for systematic assembly of experimentally

identified biochemical reactions specific to ligands, receptors, and their specific

combinations. Moreover, such high-quality datasets should be made available in

computer-readable formats to model, integrate and analyze complex biological

processes. Such networks of molecular reactions can be used to analyse cross-talks and

dynamic behaviour of signaling networks by qualitative and quantitative

experimentation and by computational modelling approaches. Acquisition of high-quality

signaling pathway data sets from the vast published literature is a tedious time-consuming

process which involves lot of planning with heuristic feasibility, established pipeline for data

acquisition, coordinators and trainers with inevitably huge man-power, and hence is a

limitation for many in the biological research world.

Pathway data in currently available public resources differs in the number of pathways,

number of components and reactions in each of these pathways, curation criteria, reaction

types, depth and coverage. Moreover, none of these resources document transcriptionally

regulated genes and their regulators in the context of specific pathways. Signaling pathways

as a platform for drug discovery is an active area of research and rely on data integrated from

multiple resources. Hence, development of resource of signaling pathways that systematically

documents reactions based on their experimental design in the published literature with their

specificity to ligand(s) or receptor(s) for broader applications is the need of the hour.

Towards this larger vision, scientists at Institute of Bioinformatics have developed a resource

of signaling pathways named NetPath/NetSlim (Kandasamy and Mohan et al., 2010 and Raju

et al., 2011) which had been widely accepted and been used for the pathway data analysis by

various software in the public domain. Scientists at IOB has expertise in coordinating

database development and biocuration as exemplified by the success of global resources such

as HPRD (Goel et al., 2012, Goel et al., 2010, Prasad et al., 2009, Mishra et al., 2006, Peri et

al., 2004, Peri et al, 2003), Human Proteinpedia (Kandasamy et al., 2009, Mathivanan et al.,

2008), Plasma Proteome database (Muthusamy et al., 2005) and Resource for Asian Primary

Immunodeficiency Diseases (RAPID) (Keerthikumar et al., 2009).

22

Here, we propose to expand the number of pathways in NetPath to host 1000 pathways with

the participation of the bioscience community in India. We also consider this a best mean to

bring about human resource development in signaling pathways in India. At the stage best

suitable for them without affecting their curriculum, involving post-graduate students would

provide them an early feel and better understanding of protein biology, advances in cellular

signaling and experimental platforms. Most importantly, the early exposure to biological

research with unique opportunity of publication would place them well above their

counterparts. The proposed effort will also lead to technology transfer across study centers

with effective capacity building for detailed understanding of signaling pathways. The

proposed community participation programme will be further extended to mathematical

modeling and development of pathway analysis suites by involving bioinformaticians from

various universities and research institutes in India. We have also initiated the experimental

validation of the currently developed signaling pathways (e.g. EGFR, TGF-beta, TSLP and

Interleukin-33) and plan to continue hypothesis-driven approaches using cutting-edge mass

spectrometry platform in the subsequent phases. We believe that data pertaining to 1000

signaling pathways in NetPath coupled to the protein information in HPRD and Human

Proteinpedia would serve as an ideal platform for the functional analysis of the human

proteome in the future.

23

16.3 Objectives

Specific Objective 1. Formation of an expert panel in signaling pathways

Development of high-quality ligand-receptor specific signaling pathways requires the active

participation of the experts of each of the pathways. This will ensure to accommodate the

evolved/evolving concepts and context specific information necessary for analysis of

signaling pathways. This panel which constitutes both national and foreign experts will

contribute as the best platform for the national human resource development

programme in signal transduction associated with this project.

Specific Objective 2. Human resource development in signaling pathways

Human resource development programme in signal transduction will be implemented at the

level of post-graduate level students in different universities in India. Through orientation

programmes, hand-on training programmes and workshops, the students will be taught the

current concepts in signal transduction. Beyond the lagging generation of text books, the

participation of the peer national and foreign experts in the domain will help us introduce

students to the current concepts and developments in protein biology and signal transduction.

Guided by domain experts, transduced through orientation lectures, hands-on training

programmes and workshops leading to publication with students as co-authors (the first of its

kind with the knowledge of what they have exactly done), is the most effective system for

human resource development in any field. We believe that our unique programme

reaching out to students of different bioscience disciplines without affecting the

curriculum will transform the educational system in India.

Specific Objective 3. Development of 1000 human signaling pathways

Scientists at Institute of Bioinformatics have developed an open-access resource of signal

transduction pathways named "NetPath". NetPath currently hosts 30 signaling pathways.

Each pathway in NetPath contains molecules and reactions with almost 10 times the data

available in any other resources in the public domain. Such limited data in other resources

does not contribute to the effective analysis of signaling pathways. Moreover, these resources

contain less than 200 through specific receptors. In the light of over 4000 receptors encoded

in the human genome, we understand that the currently available resources are not equipped

to meet the challenges of functional genomics and systems biology. In order to accelerate

basic research on signal transduction mechanisms, and to identify molecules and pathways

deregulated in diverse diseases for therapeutic approaches, we propose to develop 1000

signaling pathways in NetPath. Successful outcome of our vision would place India in the

forefront of biomedical research in the world.

Specific Objective 4. Developing a software suite to convert pathway data into standard

community data formats

The pathway data along with all the parameters associated with it should be made available in

computer readable formats to facilitate data exchange, interoperability, and analysis using

different pathway analysis software. Moreover, it is also necessary to make the data available

in different community standard formats to encompass the enhanced utility by different

research groups and bioinformaticians. Hence, we propose to develop a software suite

which would facilitate conversion of pathway data into BioPAX, PSI-MI, SBML and

GPML formats, the most widely used standard formats in the bioscience community.

24

17. Review of Current Status of research and development in the subject

International Status

Currently, there are over 325 resources available worldwide which catalogs empirical

reactions involving proteins, carbohydrates, lipids, nucleic acids, drugs, or small molecules.

Commercial signaling pathway resources are not freely available for the academic use. The

resources such as Protein lounge (www.proteinlounge.com) and BioCarta

(www.biocarta.com/index.asp) lounges colourful pathway images but only with limited

canonical pathway reactions. Pathway maps commercially developed by vendors such as Cell

Signaling Technology (www.cellsignal.com), Sigma-Aldrich (http://www.sigmaaldrich.com),

Invitrogen (http://www.invitrogen.com) and Millipore (http://www.millipore.com) are

intended to highlight their reagents and products. Primary resources with signaling pathways

developed by their own group include NetPath/NetSlim, Kyoto Encyclopedia of Genes and

Genomes (KEGG) (Kanehisa et al., 2000) (moving away from its open-source/free-

software roots to an user-pay system), Reactome (Matthews et al., 2009), Pathway

Interaction Database (NCI-PID) (Schaefer et al., 2009) (are dominated by private

enterprises and charge as much as $5,00,000 for institutional license), Signal

Transduction Knowledge Environment (STKE) (Gough, 2002), Integrating Network Objects

with Hierarchies (INOH) (Yamamoto et al., 2011), Panther (Thomas et al., 2003), and Cell

Signaling Networks Database (CSNDB) (Igarashi et al., 1997). These resources provide

pathway data in one or multiple standard formats and the quality of the data cannot be

evaluated. NetPath is unique from these resources as it contains: 1) transcriptionally

regulated genes 2) transcriptional regulators of genes, 3) cell name/type in which each

reaction is studied, 4) display of human-readable data for each pathway in one page, 5)

availability of confidence signaling pathway data filtered based on a set of confidence

criteria, and 6) availability of interactive high-confidence signaling pathway maps.

Salient features of NetPath compared with most popular resources are provided in Table 2.

Signaling

pathway

resources

File formats

available for data

download

Pathway map

features and data

download

Description of

molecules, PTMs,

cellular location

and reactions

Pathways

reviewed by

experts?

Transcriptional

regulatory

networks

available?

NetPath

BioPAX, PSI-MI, SBML,

Excel, Tab-delimited

High-confidence reaction network map in GPML,

GenMAPP, PDF, JPG and SVG

Yes Yes Yes

KEGG BioPAX KGML No No No

Reactome BioPAX, SBML, Protégé, MySQL database dump

PDF, SVG Yes Yes No

NCI-PID XML, BioPAX SVG, JPG No Yes No

Panther SBML SBGN, PNG No Reviewed by

Curation Coordinator

No

STKE - SVG No Yes No

BioCarta - No download option No Yes No

Protein Lounge - PowerPoint slides No Yes No

WikiPathways - GPML, GenMAPP,

PDF, PNG, SVG No

Pathways from multiple sources

including NetPath No

Table: 2 Salient features of NetPath compared with most popular resources in the

public domain

25

NetPath contains around ten times more molecules and reactions available in any of

these resources. All these information are available in the context of receptor-specific,

ligand-specific and ligand/receptor-combination-specific based on the experimental reports in

research articles for 1000 signaling pathways would establish NetPath as the most reliable

resource of signaling pathways in the public domain. Even with this coverage, we

acknowledge that there is more information left out due to limited man-power and ever-

increasing deposition of pathway information that will be periodically incorporated into

NetPath. Pathway data in NetPath is peer-reviewed, publicly-available, and open-

accessible resource that can be critiqued and updated by the scientific community.

Web-based community participation efforts are ongoing for resources such as WikiPathways

(Similar in principle to Wikipedia) and Panther. These web-based curation platforms aims

researchers in the field of signal transduction and do not provide extensive training to

students who lack exposure on signal transduction pathway studies. India and Japan had been

leading the efforts in resource development in Asia. With human protein resources such as

HPRD, Human Proteinpedia, and NetPath/NetSlim in India, Institute of Bioinformatics has

led the major efforts on human proteome information in India.

2 National Status

Resources for signaling pathway related information thus far developed in India include

NetPath/NetSlim from Institute of Bioinformatics and Database of quantitative cellular

signaling (DQCS) from NCBS (Shivakumaran et al., 2003). DQCS contains reaction kinetic

models of individual reactions identified in mammalian cells. However, DQCS does not

contain pathway specific information if reaction schemes, concentrations or rate constants of

individual reactions are not available. IOB is leading the efforts in characterising ligand-

receptor specific signaling pathways in India through manual annotation, analysis of protein-

protein interaction networks and by mass spectrometry based approaches to identify novel

components in signaling pathways (Mathivanan et al., 2006; Bose et al., 2006; Gandhi et al.,

2006; Amanchy et al., 2008; Harsha et al., 2008; Kandasamy et a., 2009; andasamy et a.,

2010; Demir et al., 2010; Zhong et al., 2011; Amanchy et al., 2011; Raju et al., 2011;

Nanjappa et al., 2011; Raju et al., 2011; Telikicherla et al, 2011; Goel et al., 2011; Zhong et

al., 2012; Bhattacharjee et al., 2012). IOB has also developed unique global protein resources

such as Human Protein Reference Database, Human Proteinpedia, Plasma Proteome

Database, and Mouse Protein Reference Database repositories from India. IOB is also

involved in developing Tuberculosis Reference Database as a part of TbNet India initiative in

India.

There are several research labs in India that focus on signal transduction pathways. Dr.

Upinder S. Bhalla, Neurobiology, NCBS, is a well-known expert in neurosignaling who have

developed Database of quantitative cellular signaling (DQCS). Dr. Sudhir Krishna, Cellular

Organization and Signaling, NCBS, is a renowned expert in signal transduction pathways

from India, who has extensively studied Notch signaling pathway and its role in

tumorogenesis. Dr. Mohan R. Wani from National Centre for Cell Science, Pune is an expert

on RANKL, Interleukin-3, GM-CSF, TNF-alpha signaling pathways with major focus on

their role in bone remodeling and its associated disorders. Dr. N. Srinivasan from IISc,

Bangalore is a computational biology expert for analysis of protein structure, protein-protein

interactions and prediction of protein function. Dr. Rita Christopher from NIMHANS,

Bangalore is has expertise in clinical biochemistry and neurochemistry. Dr. Nagasuma

Chandra, Bioinformatics Centre, IISc, Bangalore, is an expert in Bioinformatics. She is

applying her expertise to understand diseases and immunological processes by systems

biology approaches. Dr. K. Sekar, Structural Biology and Bio-computing, IISC, Bangalore, is

an expert in biophysics with major focus on protein sequence and structure analysis.

26

Dr. Kanury Venkata Subba Rao from International Centre for Genetic Engineering and

Biotechnology, Delhi, is a well known scientist focused in understanding the regulatory

mechanisms involved in ligand-receptor mediated signaling pathways pertaining to immune

response. Dr. Bhaskar Saha from National Centre for Cell Science, Pune, is well known for

his signal transduction research involved in T cell and dentritic cells response to infection.

Dr. Debasisa Mohanty, National Institute of Immunology, New Delhi, is a renowned scientist

primarily involved in systems biology approaches for identification of conserved network

modules and their dynamic features. Dr. G. P. S. Raghava, Institute of Microbial Technology,

Chandigarh, is a leading scientist in India known for computer Aided Protein Structure

Prediction and identification of Vaccine Candidates.

Subsequently, with the involvement of these experts in the national panel of experts on

signaling pathways, we are sure to take our community participation programme

beyond its current limits.

27

17.3 Importance of the proposed project in the context of current status

Signal transduction networks have long been identified as the platform to decipher

relationship among genes and other molecules. Ever evolving, but currently available high-

sensitive proteomics technologies potentiates identification of subtle changes in the PTM

status of proteins, fluxes in protein complexes, and dynamic protein reorganization in cells.

Pathway data available in literature put together would bring to light various novel

molecules and their reactions that are not present in other resources or are not been

covered in review articles (Figure 7).

Figure 7: Cytoscape network map of TGF beta pathway data in NetPath overlaid with

the molecules in TGF-beta pathway in KEGG. The green colour nodes represent the

molecule in KEGG for the TGF-beta pathway. NetPath contains 220 molecules and 481

reactions with all the 30 molecules and their reactions available in KEGG for this pathway.

28

A large number of molecules may not be connected to the core of the signaling networks due

to the lack of protein-protein interaction and substrate information to connect with molecules

in the core signaling pathways for which this information are available. Hence, they can be

called as orphan to specific pathways (Figure 8). This emphasizes the need for well-

structured signal transduction pathway resources as a platform to model, analyze, integrate

and visualize complex functional networks.

Figure 8: Orphan molecules in TGF beta pathway in NetPath- The maps shows the

interaction network generated by importing NetPath TGF-beta pathway BioPAX level 3.1

into Cytoscape. The nodes highlighted in yellow represents orphan proteins in the pathway.

This represents proteins that are identified to be activated/inhibited by activity assays or are

identified to have their PTM status modulated. They are defined as orphans due to their lack

of protein-protein interaction and substrate information to connect with molecules to the core

of the signaling pathways for which this information are available.

Like metabolic networks, signaling networks can be characterized by well-defined ligand-

receptor system and biological outputs assayed for their functional effects. Further, they can

be modeled to identify feedback loops and multi-step regulatory modules. Modeling also

enables estimation of the necessary parameters for hypothesis-driven experimental

approaches. Exploration of network architecture and biological implications from bottom-up

approaches requires reliable connection maps which can be constrained by expedite and

analyzed by computational approaches. Current methods for analysis of transcriptomics and

proteomics expression data to identify perturbations in signaling pathways using over-

29

representation analysis (Draghici et al., 2003), functional class scoring approaches/gene set

enrichment analysis (Ackermann and Strimmer, 2009; Subramanian et al., 2005), and

pathway topology-based approaches (Draghici et al., 2007) are highly dependent on the

amount of pathway data. Currently, data from various resources which lacks consensus

among them are brought together for this purpose. Further to the agony, pathway resources

currently available in the public domain do not incorporate the genes regulated by specific

signaling pathways, instead, they import information on the genes from various sources such

as Gene Ontology and gene regulatory network databases to provide analysis of gene

expression data in the context of specific pathways. Our reductionist approach to generate

signaling pathway data would provide an appropriate platform to analyze the integration of

multiple signals coupled to temporal fluctuation using mathematical models. Thus, a

comprehensive documentation of molecules involved in mediating specific signaling

pathways coupled to their gene regulatory networks derived from different types of

experimental platforms with a unique curation pipeline described in this project is the

need of the hour. This proposed project would accomplish the generation of the necessary

high-quality pathway data for development of more reliable and comprehensive platform for

analysis of biological data for subsequent phases of our research.

Many years have passed since Gleevec have revolutionized the treatment of chronic myeloid

leukemia. Genomic, transcriptomics and proteomics approaches have led to the identification

of various mutants, over- and under-expressed or deregulated activity of proteins associated

with different clinical phenotypes. From cell surface receptors (e.g. Receptor tyrosine

kinases, Receptor Serine/Threonine kinases, G-Protein Coupled Receptors and Ionotropic

Receptors), to intracellular proteins (enzymes, adaptors, nuclear receptors, transporters and

transcriptional regulators) common to specific biological function, there are different

perspectives to molecular targeted therapy. Components in signal transduction networks that

are identified to cross-talk with multiple pathways are long been identified as drugable targets

(Cook and McCormick, 1993; Wu et al, 1993) (Figure 9). Thus, a detailed cataloguing of

proteins and other molecules proved in mediating specific cellular response or biological

function in published research articles would serve as a centralized analysis platform

for drug discovery.

Signaling pathway reactions are studied as discrete entities using both low-throughput and

high-throughput technologies. The pathway maps currently available in text books are the

result of collection of such studies and do not introduce how they were assembled. These

maps are often interpreted as being established and does not reach out to the concepts of

complex regulatory events associated with them. One of the critical issues in biomedical

education is the challenge of being updated with the evolving concepts and technology. At

student level these are mostly accomplished by assignments or project works. However, it

takes years of focused literature search to understand the current concepts of dynamic

signaling networks, mode of development and quality of data in pathway resources, and

pathway analysis of data from various experimental platforms.

30

Figure 9: A set of research publications which highlight and discuss different signaling

pathways as therapeutic targets to combat diverse disease conditions

31

17.4 Anticipated Products & Processes of Practical/Technological utility/Socio-economic

relevance expected to be evolved by pursuing the project.

1. Human resource development in India

The proposed project will help envision, strengthen and reinforce biomedical research in

India. This will be a continued endeavor with involvement of bioinformaticians and

experimental biologists in India in the subsequent phases of our research. Over 1000 students

will be trained in the period of 4 years under this project.

2. NetPath from India as premier open-access resource for signaling pathways

facilitating systems biology approaches

Coordinated outcome of this project will result in the development of 1000 signaling

pathways publicly available through NetPath. NetPath data will be used for analysis of

experimental data in the context of specific pathways, function and diseases and would

enable systems biology approaches by the entire biomedical community. High-quality data

emanating from this project will be used to develop open-source pathway data analysis suites

and also for developing heuristic methods for the prediction of novel molecules and their

relationships in signaling pathways.

3. NetPath as a platform to identify relationships among genes and their contribution to

pathological phenotypes

A detailed characterization of molecules and their reactions that synchronize cellular funct ion

would accelerate research and enable identification and attribution of function to a large

number of molecules in specific pathways. These molecules can be selectively validated for

their therapeutic applications.

4. NetPath community participation programme as a platform for collaborative efforts

The network and association developed between premier educational and research

organizations in India would enable technology transfer and interventions channelizing

targeted and broader scientific endeavors in the future.

32

18. Work Plan (Incase for multi institutional projects, work plan, role & responsibility

of each institute to be given separately)

Responsibility of co-investigators in this community participation project is summarized in

Table 3.

Participating Institute Project Leaders from

Participating Institutes Responsibilities

Anna University Dr. P. Gautam

(Centre for Biotechnology)

Organization and facilitation of orientation programmes, workshops,

training and biocuration

Pondicherry University

Dr. Archana Pan and Dr. P. P. Mathur (Centre for Bioinformatics)

Organization and facilitation of

orientation programmes, workshops,


Madurai Kamaraj

University

Dr. P. Gunasekaran and Dr. G

Kumaresan (Department of Genetics)

and Dr. S. Krishnaswamy

(Department of Genetic Engineering)



University of Pune

Dr. Urmila Kulkarni-Kale, Sangeeta

Sawat, and Dattatraya Desai

(Bioinformatics centre)




University of Kerala

Dr. Achuth Shankar

(Computational Biology and Bioinformatics)


orientation programmes, workshops, training and biocuration

Armed Forces Medical

College

Dr. S. Shankar and Dr. Velu Nair

(Department of internal medicine)



Mangalore University

Dr. K. K. Vijayalaxmi, Dr. K.

Bhasker Shenoy (Department of

applied Zoology) and Dr. Prashantha

Naik (Department of Biosciences)



Central University of Kerala

Dr. Sameer Kumar

(Biochemistry and Molecular

Biology)




Kuvempu University

Dr. Riaz Mahmood and H. S. Santosh Kumar (Department of Post-Graduate

Studies and Research in

Biotechnology and Bioinformatics)


orientation programmes, workshops, training and biocuration

University of Mysore

Dr. H. S. Prakash, Dr. K. R. Kini, and

Dr. Geetha N Prashanth,

(Applied botany and Biotechnology)




Table 3: Role and responsibility of the co-investigators from the Participating Institutes

33

18.1 Methodology

Specific Objective 1. Formation of an expert panel in signaling pathways

The first step to accomplish this project will be to identify national or international experts on

that particular signaling/ligand receptor system/signaling pathways. The experts who have

worked on specific pathways for more than 6 years will be selected as potential authorities of

the pathway. They will be contacted for their approval to become the pathway authorities.

Once approved, we will seek their suggestions on the pathway maps to expedite the

development of respective pathways. The interaction between the pathway authorities and the

coordinators of this project will enhance the development of the pathways accommodating

the current concepts and broad opinion in the field. These experts will constantly work with

the annotators, reviewers and the university faculties to ensure generation of high quality

pathway data. They will also be actively involved in periodically updating the information in

the resource. The involvement of world experts in both the generation and updation

processes of pathways will help keep the faculty as well as others involved in the project

to be up-to-date with the latest concepts and developments in signal transduction

research. The current list of signaling pathway experts on board as pathway authorities are

provided below (Table 4).

Pathway authority Designation/Department/Institute Signaling

pathway

Foreign members

Dr. William P.

Schiemann

Associate Professor, General Medical Sciences

(Oncology), Case Comprehensive Cancer Center, Case

Western Reserve University, USA

TGF beta

Dr. Mark Knepper Principal Investigator, Epithelial Systems Biology

Laboratory, National Heart Lung and Blood Institute, USA

Arginine

vasopressin

Dr. Carrie Shemanko Associate Professor, Department of Biological Sciences,

University of Calgary, Canada Prolactin

Dr. Anirban Maitra Professor, Pathology and Oncology, The Johns Hopkins

University School of Medicine, USA AXL

Dr. Gerald J. Atkins

Professor and Head, Bone Cell Biology Group, NHMRC

RD Wright Fellow Discipline of Orthopaedics and Trauma,

University of Adelaide, Australia

TNF-related

weak inducer of

apoptosis

Dr. Jun Zhong

McKusick-Nathans Institute for Genetic Medicine and

Departments of Biological Chemistry, Pathology, and

Oncology, The Johns Hopkins University School of

Medicine, USA

Thymic stromal

lymphopoietin

Dr. Ge Ruowen Associate Professor, Department of Biological Science,

National University of Singapore, Singapore Angiopoietin

Dr. Stephen Desiderio Professor, Department of Molecular Biology & Genetics,

Johns Hopkins School of Medicine, USA B cell receptor

Dr. Jon C.D. Houtman Assistant Professor, Department of Microbiology, Carver

College of Medicine, University of Iowa, USA T cell receptor

Dr. Warren J. Leonard Laboratory of Molecular Immunology

National Heart, Lung, and Blood Institute, NIH, USA Interleukin-2

Dr. Stefan

Constantinescu

Principal Investigator, The Ludwig Institute for Cancer

Research, Brussels Branch and the Experimental Medicine

Unit, Christian de Duve Institute of Cellular Pathology,

Universite Catholique de Louvain, Belgium

Interleukin-3

34

Dr. Masato Kubo

Principal Investigator, Research Institute for Biological

Sciences, Tokyo University of Science. Signal/Network

Team, RCAI, RIKEN Yokohama Institute, Japan

Interleukin-4

Dr. Osamu Ohara Head of Department, Laboratory for Immunogenomics,

RCAI, RIKEN Yokohama Institute, Japan Interleukin-5

Dr. Toshio Hirano

Professor, Laboratory of Developmental Immunology,

Graduate School of Frontier Biosciences and Department

of Molecular Oncology, Graduate School of Medicine,

Osaka University and Laboratory for Cytokine Signaling,

Japan

Interleukin-6

Dr. Jean-Christophe

Renauld

Principal Investigator, The Ludwig Institute for Cancer

Research, Brussels Branch and the Experimental Medicine

Unit, Christian de Duve Institute of Cellular Pathology,

Universite Catholique de Louvain, Belgium

Interleukin-9

Dr. Eva Dimitriadis Associate Professor and Head, Embryo implantation

Laboratory, Prince Henry's Institute, UK Interleukin-11

Dr. Toshio Hirano

Professor, Laboratory of Developmental Immunology,

Graduate School of Frontier Biosciences and Department

of Molecular Oncology, Graduate School of Medicine,

Osaka University and Laboratory for Cytokine Signaling,

Japan

Interleukin-17

National members

Dr. Akhilesh Pandey

Director, Institute of Bioinformatics, Bangalore, India.

Professor, McKusick-Nathans Institute for Genetic

Medicine and Departments of Biological Chemistry,

Pathology, and Oncology, The Johns Hopkins University

School of Medicine, USA

EGFR, EPO,

TGF beta,

Interleukin-7,

TSLP

Dr. Mohan R. Wani Scientist-E, Lab1, Cell Biology, National Centre for Cell

Science, India RANKL/RANK

Dr. Srabani Mukherjee

Scientist C, Department of Molecular Endocrinology,

National Institute for Research in Reproductive Health,

India

Follicle

stimulating

hormone

Dr. P. P. Mathur

Professor and Head, Department of Biochemistry &

Molecular Biology and Bioinformatics Centre, School of

Life Sciences, Pondicherry University, India

Thyroid

stimulating

hormone

Dr. S. N. Umathe

Professor and Head, Department of Pharmaceutical

Sciences, Rashtrasant Tukadoji Maharaj Nagpur

University, India

Corticotropin

releasing

hormone

Dr. P. R. Sudhakaran Professor and Head, Department of Biochemistry,

University of Kerala, India

Advanced

glycation end-

products

Dr. G. Anilkumar Associate Professor, School of Biotechnology, Amrita

Vishwa Vidyapeetham, India Leptin

Dr. Sujay K. Singh President/CEO, IMGENEX INDIA Pvt. Ltd.,

Bhubaneswar, India Interleukin-1

Dr. Sudhir Krishna Cellular Organization and Signaling, NCBS, India Notch

Table 4: The current list of national and foreign signaling pathway experts on board

35

Specific Objective 2. Human resource development in signal transduction

IOB had already partnered with Pondicherry University, University of Pune, University of

Mysore, Kuvempu University, and Armed Forces Medical College (Pune) for this

programme. Our initial effort led to the training of over 200 post-graduate students from

these institutes and has also to the development of 20 signaling pathways (table 1). With the

success of our social experiment with these institutes, several departments from various

universities such as Jawaharlal Nehru University, Madurai Kamaraj University, Anna

University, Mangalore University, Bangalore University, University of Kerala, Central

University of Kerala have consented to become a part of this effort.

The students from Central University of Kerala will be involved to engage them in

community efforts and help the University emerge from their initial stage of establishment.

The signal transduction related topics in their curriculum will also be completely covered in

this process.

The participation of research institutes such as NIMHANS and NIRRH would enable

bridging between clinicians and researchers. Moreover, this will also provide a platform for

technology transfer and future collaborations. Students from these Institutes will be

entertained to participate in this programme in the subsequent phases as well.

The MBBS students from AFMC will participate in this effort as a part of the ongoing

collaboration efforts. MBBS students from other medical colleges who approach us (For

example: students from Indian Medical Students Association) will also be enrolled in this

human resource development programme in signaling pathways. This will provide a

platform to develop a prospectus layer of next generation students well-versed to take

research to translational medicine.

2.1. Orientation programmes at Participating Institutes

Workshops will be conducted every year at Participating Institutes to recruit and gather

participation of other universities and institutes in India.

Investigators from IOB along with Project Leaders from current and prospective Participating

Institutes will organize pathway orientation programmes. The students and faculties from all

the biosciences departments will be invited. During these sessions, students will be exposed

to the concepts of signaling pathways, and experimental methods involved in the

investigations of signaling pathways including protein-protein interactions, enzyme-substrate

reactions, various post-translational modifications, gene expression analysis platforms, and

transcriptional regulatory networks. Students will also be introduced to diverse types of data

resources developed by IOB and importance data resources in Systems Biology approaches.

In this process, they will also be introduced to various pathway editing, visualization and

analysis software and the criteria used to develop high-confidence signaling pathway maps

using PathVisio, Cytoscape, GenMAPP and Cell Designer.

2.2. Recruitment of students for Human Resource Development network in building

human signaling pathways

Based on the interactive sessions with the students, along with the involvement of Project

Leaders, 15 to 20 students motivated preferably in their Second year of M.Sc. will be

recruited into this programme. This will take into account the interest of the students,

willingness of their head of the department(s), and duration of the semester break period

available. The recruited post-graduate students will participate in this program during their

36

semester breaks. Some students can also use this opportunity for dissertation work if allowed

from their respective departments/universities. Students who have completed or are

pursuing their MBBS/M.Sc. course from different Universities and Institutes in India

will also be considered, if they apply. In all, 200 to 250 students will be recruited in the

programme per year.

2.3. Training in the development of human signaling pathways at IOB

Students will stay for about 60 days at IOB and will be trained in the development of specific

signaling pathways. Training modules for this programme includes,

1. Ligands and their receptors, methods to stimulate the activity of receptors, concept of

agonists and antagonists, and transfection and overexpression of receptors.

2. In vivo/in vitro methods to study protein-protein interactions (yeast-2-hybrid,

mammalian-2-hybrid, co-precipitation, fluorescence resonance energy transfer,

bioluminescence resonance energy transfer assays coupled to identification of

interacting proteins (immuno- and recombinant DNA- based technology, and by mass

spectrometry)

3. In vivo and in vitro assays to detect enzyme-substrate reactions, post-translational

modifications, protein activity assays, use of mutants to identify the site of

modifications, and mapping of specific site and residues to RefSeq protein accession.

4. Identification of protein localization in different cellular compartments

5. Introduction to experimental platforms such as microarrays, northern blotting, in-situ

hybridization, serial analysis of gene expression, and PCR-based methods to study

gene expression at transcriptomics level.

6. Documentation of pathway specific reactions in PathBuilder following NetPath and

NetSlim criteria (as described by Raju et al., 2011).

7. Usage of Controlled Vocabularies including GO, EVOC, PSI-MS and International

pathway data exchange formats such as PSI-MI, BioPAX, SBML and GPML.

8. Formulation of query terms to search for pathway reactions using PubMed

9. Effective screening for relevant research articles pertaining to specific pathways

Initially, students will be demonstrated the documentation of pathway reactions by faculty

level scientists at IOB. Each student will be provided with research articles for hands-on

training. They will also be trained to review pathway reactions captured by another set of

students. Each reaction will be reviewed by IOB researchers. Review comments will be

explained to students. By subsequent cycle of this process, we will ensure their confidence

and error-free as possible documentation of pathway reactions.

Every year, students will be trained to participate in the development of a set of 150

pathways. The certificates will be issued to all the students who participate in this

programme.

2.4. Remote monitoring of human signaling pathway development by students

The research articles for each pathway will be screened by trained scientists at Institute of

Bioinformatics. Specific pathways will be allotted to individual students or a group of two/

three, depending on the number of students and their provisional time available for literature

analysis. Accordingly, during their summer vacation, or if interested to take up NetPath

project as their summer training project, students will visit IOB and their progress will be

directly monitored by faculty scientists. Otherwise, their documentation will be remotely

monitored through PathBuilder, Skype conferences, and/or coupled with frequent visit to

37

universities or research institutes. The full text articles which are not open-access will be

provided.

2.5. Development of signaling pathway maps by students

The students will be trained to develop pathway models using various pathways editing

software such as GenMAPP, Cytoscape, PathVisio and Cell Designer. The pathway data

assembled by students, reviewed by experts at IOB, will be integrated into NetPath. The

students who have contributed to development of each pathway in NetPath will be listed

under curators.

2.6. Training students on preparation of manuscripts of specific signaling pathways

The students will be trained to prepare specific pathway manuscripts. The students and

Project Leaders from their respective Participating Institutes will be authors in these

manuscripts. These manuscripts will be edited and reviewed by faculty scientists along with

specific pathway reviewers at IOB. Scientists across the world at the level of professor or

associate professor who have expertise on specific pathway exemplified by the publication

will be invited as pathway authorities. The pathway authority for a signaling pathway will

review the pathway data to ensure data as error-less as possible and ensure the inclusion of

majority of molecules identified in a pathway and also whether studies from major labs

involved in the pathway are incorporated. The manuscripts will be submitted to international

journals for peer-review and publication.

Specific Objective 3. Development of 1000 human signaling pathways

We have already established a resource of signaling pathways named NetPath. NetPath

currently hosts 27 signaling pathways and more than 100 pathways are currently under

development with internal funding. The reactions in NetPath pathways encompass

spatiotemporal biochemical reactions induced by the interaction of specific ligands to their

receptors reported in published research articles. These reactions include protein-protein

interactions, enzyme-catalysis reactions, post-translational modifications, activation-

inhibition reactions and protein translocation events. We have identified over 1000 ligand-

receptor mediated signaling pathways for which pathway specific information are available in

literature.

3.1. Curation of protein-protein interactions

Proteins mediate cellular signaling by protein-protein interactions (PPIs) and protein-non-

protein interactions. PPIs experimentally proved to be stimulated in a pathway will be

documented as binary or complex interactions. Binary interactions correspond to PPIs when

only two proteins involved in complexes are identified. More than two proteins associated in

complexes, when identified by western blotting or by mass spectrometry, the proteins

together are documented as a complex. It should be noted that, the proteins may directly

interact with each other or may be indirectly associated with their stoichiometry of reaction

not devised. This information would provide an ideal platform to integrate more proteins

that may be identified in the future to be part of dynamic complexes. For every interaction,

we will also document domains/motifs, post-translational modifications (PTMs), and

subcellular localisation, whenever reported. PPIs identified in mammalian cells other than

human will also documented if the interactions were never studied in human. This would

facilitate experimental validation in human system. Further to support this information, we

will also catalogue the species of each interaction molecules (whether human, mouse, rat,

38

bovine or other mammals) along with the cell/cell line information in which the reactions

were studied. Most of the PPIs studies often involve transfection and expression of receptors

or intracellular proteins from other species. Thus, this information would provide a valuable

tool for the researchers to experimentally replicate and analyse the difference in species

specific interactions. A textual description with the above information will also be

documented for each reaction.

3.2. Curation of enzyme-substrate reactions and post-translational modifications

Array of dynamic PTMs determines the spatiotemporal organization of proteins and their

activity. We will document experimentally derived information on the enzymatic reactions

modulated in signaling pathways. High-throughput experimental platforms capable of

profiling global changes in PTM status of proteins have revolutionised protein biology. This

has led to the emergence of phosphoproteome, acetylome and methylome analogous to the

traditional proteome or genome. The temporal and context-specific studies thus accounting

for the heterogeneous datasets published literature form the basis for analysis of the fluxes in

cellular signaling. Hence, we will catalogue catalytic reactions involving an enzyme and its

substrate as direct and enzyme-unidentified PTM reactions as 'induced'. This classification is

devised based on the concept that an enzyme may have multiple substrates and vice versa.

The PTMs for which high-throughput experimental platforms are currently available such as

phosphorylation, dephosphorylation, sumoylation, desumoylation, ubiquitination,

deubiquitination, acetylation, deacetylation, proteolytic cleavage, methylation,

demethylation, palmitoylation and glycosylation will be focussed more in this effort. The

influence of PTMs on the activity of proteins whether activated or inhibited in the context of

the study will also be documented. Identification of site of PTMs mostly depends on the

availability of site-specific antibodies, site-directed mutagenesis approaches, and analysis by

mass spectrometry. Such information is often reported with the sites mapped to one or other

protein isoforms or based on the antibody information. Hence, whenever site and residue

information are available for PTMs, we will map them to either the specific or longest

isoforms in the current version of the RefSeq protein database.

3.3. Protein translocation

The variations in spatiotemporal distribution of proteins across cellular compartments to

mediate signaling events will be cataloged in this category. The PTM dependence or

molecular interactions underlying these events will also be documented along with the sub-

cellular compartments in accordance with Gene Ontology controlled vocabulary (Ashburner

et al., 2000).

3.4. Genes transcriptionally regulated by signaling pathways

Differential responses to stimuli are brought about by temporal changes in gene expression.

Qualitative and quantitative changes observed at mRNA level are determined by

transcriptional regulatory networks. We will document genes which are experimentally

identified to be regulated at mRNA level in humans by specific pathways. This will be

documented from mRNA profiling studies employing cDNA microarrays and non-microarray

approaches such as northern blotting, PCR-based methods, in-situ hybridization and

ribonuclease protection assay. A minimum fold change value of 2 and p-value of < 0.05 will

be taken as arbitrary cutoffs for inclusion of gene expression data from microarray studies.

Further, name of cells or cell types in which the genes are identified to be up- or down-

regulated by specific pathways will be also documented.

39

3.5. Identification of transcriptional regulators

We will capture transcription regulators (transcription factors, or their co-activators/co-

repressors) of the genes whose expressions are regulated by specific pathways. Such

transcriptional regulators will be included only if they are proved using chromatin

immunoprecipitation assay, electrophoretic mobility shift assay, gene silencing, and promoter

activity assays in specific pathways.

3.6. Protein expression regulated by signaling pathways

Identification of protein expression regulated by specific pathways would contribute to a

better understanding of proteome reorganization and functional response of cells to specific

stimuli. The proteins up- or down- regulated by specific signaling pathways will be cataloged

along with the information on the cell system.

3.7. Development of a high-confidence graphical regulatory map of signaling pathways

Composite maps of signaling events are often used to visualize, hypothesize and to develop

mathematical models to predict the behaviors of normal and diseased cells. Moreover,

signaling maps are also overlaid with biological data from various high-throughput

experimental platforms to obtain an integrated view of biological processes. There were

numerous molecules and reactions in NetPath which were not included in existing pathway

models or signaling maps available elsewhere (e.g., induced PTMs discussed under enzyme-

substrate reactions and post-translational modifications). Most of these molecules remain

unconnected to the core network due to lack of information on the interaction partners,

upstream enzymes or downstream effector molecules and hence can be called a novel

molecules in the pathway. All the information for a specific pathway in NetPath will be made

available in standard formats that can be used to visualize the networks using various

visualization and analysis software such as PathVisio, GenMAPP, GO-Elite, and Cytoscape.

However, to reduce the complexity and to provide effective visualization, we will develop

network maps for each signaling pathway by applying a set of confidence criteria.

3.7.1. Analysis of high-confidence reactions in NetPath pathway

We will apply the following inclusion criteria to extract a high confidence set of reactions

from each of the pathways in NetPath as described in (Raju et al., 2011): (a) reactions

supported by at least 2 research articles; (b) reactions such as PPIs reported through high-

throughput analyses, as well as PTMs identified using mass spectrometry provided that they

are validated by a focused experiment; (c) components of known protein complexes; (d)

molecules or reactions established through expert review articles; and (e) direct PPIs

provided they are derived from both in vitro and in vivo experiments.

3.7.2. Graphical Representation of NetSlim

All molecular reactions that occur downstream of activated receptors will be represented by

solid edges, which depict direct interactions/reactions, or by broken edges, which depict

indirect/induced events. Signaling nodes will be depicted based on the ability of molecules to

interact with their partners, and on the availability of protein regulators to cross-talk with

other signaling modules. The topology of the pathway, which determines whether a given

molecule lies upstream or downstream from another reference molecule, will be determined

based on the biological information obtained from studies using mutants,

activators/inhibitors, knock-out and silencing approaches. The edges which represent various

40

PPIs, enzymatic reactions, or protein translocation events will be distinguished by distinct

colors. Detailed legends will be provided in all the pathway maps.

Specific Objective 4. Development of a software suite to convert pathway data into

standard community data formats.

We have developed PathBuilder, an open-source web application to annotate biological

information pertaining to signaling pathways. PathBuilder enables annotation of molecular

events including protein–protein interactions, enzyme–substrate relationships, protein

translocation events and gene regulation. The PathBuilder should be enabled to accomplish

extensive curation, review and constant revision of pathway by community participation.

This demands that there should be provision to store various query terms, accessibility to

students of participating centers, list of articles curated, period when pathways were last

updated, and to facilitate internal review and review by pathway authorities Availability of

Pathway data in NetPath and NetSlim in computer-readable formats such as BioPAX, PSI-MI

and SBML are essential for data exchange and interoperability with available pathway

analysis software. Current version of PathBuilder does not facilitate automated conversion of

pathway data into these formats pathways. PathBuilder tool should also undertake various

quality control measures and consistency checks of curation by at student level. Taking into

account the large number of pathways, we propose to enable provisions for constant revision,

quality control measures and automated export of pathway data into BioPAX level 3.0, PSI-

MI version 2.5 and SBML version 2.1 formats.

41

18.2 Proprietary/patented items, if any, expected to be used for this project.

No other proprietary or patented item will be used for this project.

18.3 Organization of work elements

Dr. Keshava Prasad, Dr. Akhilesh Pandey and Dr. Rajesh Raju will coordinate the

implementation of overall program between IOB and all Participating Institutes. Coordinators

along with Dr. Sowmya Soman and Dr. Aditi Chatterjee and the Research Associates

appointed in this project will provide the orientation programme, selection of students and

training for the development of signaling pathways. Project Leaders from Participating

Institutes will coordinate orientation program, workshops and monitor curation of signaling

pathways of their students in the respective Participating Institutes. Dr. Prasad, Dr. Raju, Dr.

Pandey, Dr. Chatterjee, Dr. Soman and all Project Leaders from Participating Institutes will

be involved in the development of publication quality work emanating from the program. The

Project Leaders from each of the institutes will coordinate this human resource development

programme in their respective institutes. The network of organization of work elements by

the nodal centre (IOB) with the Participating Institutes are provided in Figure 10.

Figure 10: The current, new and prospective Participating Institutes in the human

resource development programme on signaling pathways- The current Participating

institutes are in light blue color. The new and prospectively future Participating Institutes are

colored in dark blue.

42

Two Research Associates and 10 Senior Research Fellows recruited for this programme will

be trained by Faculty Scientists and Research Scientists from IOB. The research scientists,

Research Associates and the Senior Research Fellows will be involved in the initial screening

of the articles for pathways specific to ligands or specific ligand-receptor combinations. A

basic query term will be used to screen for articles containing pathway information on

specific pathways (e.g. 'epidermal growth factor' along with its other MeSH terms will be

used to screen articles for EGF pathway) to increase the coverage of literature survey. Based

on the number of articles to be screened for curation of specific pathways, pathways are

categorized into 5 different groups containing- (i) 100 to 500 articles to be screened, (ii) 500

to 1000 articles to be screened, (iii) 1000 to 3000 articles to be screened, (iv) 3000 to 6000

articles to be screened, and (v) more than 6000 articles to be screened. In the first year, 10

research scientists from IOB will be involved with 2 Research Associates and 10 Senior

Research Fellows in screening the articles.

The overall workflow of the components involved in this project is outlined in Figure 11.

The screened articles will be distributed to the students on an average of 100 research articles

per student. Wherever there are more than 100 articles to be curated, more students will be

allocated a pathway with every student per further 100 further articles. Over 100 pathways

will be chosen according to the number of articles to be curated so as to accommodate all the

students as co-authors in publication. After their initial curation required for the respective

manuscripts, the students can also work on other pathways in which the students can be co-

authors, thus, would ensure effective time-management and dedication to pathway

development process by the students. Reaction curated by students will be reviewed by

specific reviewers (research scientists from IOB, Senior Research Fellows and Research

Associates) every day to make sure that the curation criteria is clear and also will be

discussed with all the students so that students may not repeat the mistakes again and again.

Over a period of one month, the students (in cases where more than one student is involved in

a pathway) will also be assessed by inter-review of curation amongst themselves. The

authorship position of students will be based on the dedicated time and quality of the

literature analysis by each and every student(s) analyzing specific pathways.

The students will also be introduced to the manuscript preparation process during their

literature analysis. Manuscript preparation will be initiated from the initial process of seeking

pathway information pertaining to specific signaling pathways from review articles. More

information will be furnished into the manuscript as and when they analyze more research

articles which study signaling pathways in the context of their function in different cell types

and molecules of therapeutic interest. This process would also help them define and interpret

pathway reactions in the manuscript based on the results obtained from various experimental

platforms.

The pathway reactions obtained by literature analysis will be further filtered using the

NetSlim criteria. Further PubMed search using the specific molecules involved, in

combination with the name of specific ligands and/or receptors will also be carried out at this

stage to ensure comprehensiveness and effective application of NetSlim criteria. The filtered

reactions will be graphically represented in a topological manner using PathVisio by the

students with the help of their respective mentors. The information obtained from silencing,

mutant, activator/inhibitor approaches will be used to device the relationships amongst the

molecules as to whether a molecule is upstream or downstream to another molecule in a

pathway and also to identify positive and negative feedback regulations. The international

experts on specific pathways will also be selected from the articles which had been curated

based on the number of articles and their current focus. They will be requested and invited to

become the pathway authority for specific pathways. The comments from the pathway

authority will be incorporated in the pathway resource as well as the manuscript. The

43

pathway data will be released into the public along with the data in standard community

formats for the review by the peer-reviewers assigned by international journals.

Figure 9: An overview of the sequential process involved in the development of 1000

signaling pathways.

Figure 11: The overall workflow of the components involved in this project

44

18.4 Suggested plan of action for utilization of research outcome expected from the

project.

1. The development of signaling pathways by the student bioscience community would

generate a cream of interdisciplinary scientists who would pace up with evolving technology

and reinforce technological development in biomedical research and education in India.

2. Human resource development programme for signaling pathways with the involvement

of scientists from various research institutes in India would facilitate technology transfer and

mutual collaborative efforts for the next phase of the research on signaling pathways as well

as on different technology platforms.

In continuation, the high-quality data emanating from this described project will be used for

the computational analysis and to develop open-access pathway analysis suites. This phase

will involve eminent bioinformaticians and their students from different institutes in India.

The outcome of predictions will be validated experimentally and further hypothesis-driven

approaches will be undertaken to study cross-talks and temporal behavior of signaling

networks (Figure 12).

Figure 12: A diagrammatic representation of the three-tier components originating with

this proposal

45

3. NetPath will serve as an initial platform to integrate signaling pathways involved in

specific biological processes.

4. The pathways in NetPath would enable integration and analysis of cell/cell type specific

information which is currently not available in any other resources in the public domain.

5. Thousand signaling pathways that will be publicly available in NetPath

(www.netpath.org) with additional information linked to Human Protein Reference Database,

Human Proteinpedia and NCBI will serve as a unique platform for systems biology

approaches.

6. Information in NetPath would accelerate research on specific signaling pathways and

identification of missing links and relationships of several orphan molecules.

7. The molecules and their reactions in 1000 signaling pathways will form the basis for

prediction and validation of several known and novel molecules as potential therapeutic

targets for diseases.

8. NetPath pathways enriched based on specific functions and disease processes would

enable network approaches to identify key components that cross-talks in signaling networks.

46

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55

18.5 Time schedule of activities giving milestones. (Physical/Scientific separately)

S.

No. Milestone (physical)

Expected

Start

(Month/Year)

Expected

Completion

(Month/Year)

1.

2.

Establishing computational facility exclusively

for the community participation programme at

participating institutes

Recruitment of Research associates and Senior

Research Fellows

0-3 months

0-3 months

S.

No. Milestone (Scientific)

Expected

Start

(Month/Year)

Expected

Completion

(Month/Year)

1.

2.

3.

4.

5.

Orientation, workshops, monitoring and

internal assessment of biocuration

Internal review of reactions curated in specific

pathways

Development of NetSlim maps for each

pathways

Data integration into NetPath, NetSlim and

WikiPathways

Manuscript preparation and review by pathway

authorities

Every Year

Every Year

Every Year

Every Year

Every Year

56

19. Name and address of 5 experts in the field

Name & Designation Address Email

Dr. G. P. S. Raghava

Scientist & Head

Bioinformatics Centre, Institute

of Microbial Technology,

Sector-39A, Chandigarh-

160036

[email protected];

[email protected];

[email protected]

Dr. Indira Ghosh,

Professor and Dean

School of Information

Technology, Jawaharlal Nehru

University, New Delhi -110067

[email protected]

Dr. Sudhir Krishna,

Professor

National Centre for Biological

Sciences, Tata Institute of

Fundamental Research, GKVK,

Bellary Road, Bangalore-560065

[email protected]

Dr. Debasisa Mohanty

Scientist

Bioinformatics Center, National

Institute of Immunology,

Aruna Asaf Ali Road,

New Delhi- 110067

[email protected]

Dr. N. Srinivasan

Faculty

Molecular Biophysics Unit,

Indian Institute of Science,

Bangalore – 560012

[email protected]

57

PART IV: BUDGET PARTICULARS

20. Budget (In Rupees)

Name of the Institute Amount of Budget

1 Institute of Bioinformatics, Bangalore Rs. 7,54,95,802/-

2 University of Pune Rs. 9,43,000/-

3 Pondicherry University Rs. 9,43,000/-

4 Madurai Kamaraj University Rs. 9,43,000/-

5 University of Mysore Rs. 9,43,000/-

6 Kuvempu University Rs. 9,43,000/-

7 Mangalore University Rs. 9,43,000/-

8 University of Kerala Rs. 9,43,000/-

9 Central University of Kerala Rs. 9,43,000/-

10 Armed Forces Medical College Rs. 9,43,000/-

11 Anna University Rs. 9,43,000/-

Total Rs. 8,49,25,802/-

The imbalance in the assigned budget across Institute of bioinformatics (IOB) and the

Participating Centres are due to the following aspects:

1) The fellowships of 2 Research Associates and 10 Senior Research Fellows to execute the

human resource development programme with the Participating Centres will be conferred by

IOB.

2) The training of over 130 students from the Universities is hosted at IOB. The allowances

pertaining to their travel, accomodation, food and training will be provided by IOB. The

Participating centres will confer training only to 5 students (handicapped students or students

who are not in a position to travel to Bangalore under certain circumstances) and further

coordinate and facilitate this human resource development programme in signal transduction.

3) The hardware and the software required for the development of pathways at IOB will be

provided by IOB.

4) Two conferences with the participation of 10 leaders in signal transduction around the world

will be coordinated and organized by IOB. The expenses include travel and accommodation

of the experts and the overall organization charges to conduct these conferences.

5) The charges for the publication of over 400 pathways in various international peer- reviewed

journals will be met by IOB.

6) The travel expenses of the coordinators, investigators, 2 Research Associates and 10 Senior

Research Fellows from IOB to the current 10 Participating Centres and the prospectively

new centres for the orientation programmes and hands-on training workshops will be met by

IOB.

58

20. Budget (In Rupees) (Institution wise):

Institute of Bioinformatics, Bangalore A. Non-Recurring

S. No. Item Year 1 Year 2 Year 3 Year 4 Total (INR)

1 High efficiency Netapp FAS 2020 storage server x 1 nos. 15,50,550 15,50,550

2 Windows Work station with advanced configuration x 20 nos. 19,71,930 19,71,930

3 Windows PCs x 30 nos. 11,49,375 11,49,375

4 Interactive white board x 1 nos. 1,82,500 1,82,500

5 Canon Digital Copier Model iR 2525 1,50,865 1,50,865

Total 50,05,220 50,05,220

Sub-Total (A) = Rs. 48,11,670/-

Justification:

i) High efficiency Netapp FAS storage server- is required to store large amount of data pertaining to signaling pathways. At a given point of

time, more than 50 students from various Participating Institutes, Senior Research Fellows and Research Associates will be working to develop

signaling pathways.

ii) Windows Work station with advanced configuration x 20 nos and Windows PCs with basic configuration- are required for the

biocurators and bioinformaticians to annotate and review pathway data and also to convert the data into community standard formats. Further, it

is neccessary to represent pathway graphically in the form of high-end pathway images in different formats using several visualization software.

iii) Interactive white board - allows keeping notes and annotations as an electronic file for later distribution either on paper or through a

number of electronic formats. It facilitates integration of pathway diagrams, spreadsheet or text from a Microsoft Word file for effective and

illustrative orientation and training modules for the development of signaling pathways.

iv) Canon Digital Copier Model iR 2525- is required to prepare the training modules and assignments for the students from Participating

Institutes.

59

B. Recurring

B1. Manpower

Position No Consolidated Emolument +

allowances Year 1 Year 2 Year 3 Year 4 Total (INR)

Research Associates (2) Rs. 22000 + 30% HRA 6,86,400 6,86,400 6,86,400 6,86,400 27,45,600

Senior Research Fellows

(10) Rs. 18000 + 30% HRA 28,08,000 28,08,000 28,08,000 28,08,000 1,12,32,000

Trainees from current

participating centers

(130 per year)

Fellowship (Rs. 5000/- per month),

travel allowance (onetime Rs. 2000/-),

food allowance (Rs. 5000/- per month)

and accommodation (Rs. 8000/- per

month) for trainees -

(Total: Rs. 38,000/- for 60 days)

49,40,000 49,40,000 49,40,000 49,40,000 1,97,60,000

Trainees from other

institutes (50 per year)

Fellowship support

(Total: Rs. 15,000/- for 60 days) 7,50,000 7,50,000 7,50,000 7,50,000 30,00,000

Total 63,34,400 63,34,400 63,34,400 63,34,400 3,67,37,600

Sub-Total (B.1) = Rs. 3,67,37,600/-

Justification:

i) Research Associates (2) - Research associates (M.Sc./Ph.D.) who have a minimum of 2 years experience in biocuration (with one or two

publications relevant to biocuration) will be recruited. RAs will be involved in the training of the Senior Research Fellows along with the

investigators. Each Research associate will be involved in training students from 5 different Participating Institutes every year.

ii) Senior Research Fellows (10) - Trained Senior Research Fellows will be responsible for training students from each Participating Institutes

every year. They will be involved in screening research articles pertaining to each signaling pathway, providing full text research articles, direct

and remote monitoring of the biocuration by students, review of pathway data, development of signaling pathway maps for each pathway and

preparation pathway manuscripts. Each Senior Research Fellows will be involved in this process to develop more than 10 signaling pathways

with a Participating Institute every year.

60

iii) Trainees from participating centres will visit IOB during their holidays or summer vacations and will be under direct training at IOB for a

period of 2 months every year. This will facilitate effective focused training sessions at IOB by the faculty scientists and Senior Research

Fellows at IOB. A fellowship of Rs. 5000/- per month, food allowance of Rs. 5000/- per month and accommodation charge of Rs. 8000/- per

month will be provided for the respective categories based on the living cost in Bangalore. Further, an onetime payment of Rs. 2000/- on an

average will be provided towards their travel allowance to and fro to Bangalore and their respective Universities. This will promote the active

participation of the students from the Universities beyond the apprehension of expense of travel, food and accommodation in Bangalore.

iv) Trainees from other Institutes will be selected based on the applications from different colleges and Universities for summer training and

also from various medical students for short term exposure to development of signaling pathways. A fellowship of Rs.15000/- for a total of 60

days will be provided as support.

B.2 Consumables

Item Year 1 Year 2 Year 3 Year 4 Total (INR)

1 Conferences and workshops - 30,00,000 - 30,00,000 60,00,000

2 Open access charges for publications 55,00,000 55,00,000 55,00,000 55,00,000 2,20,00,000

3 Partial internet charges 50,000 50,000 50,000 50,000 2,00,000

4 Microsoft Windows 7 Pro 32 bit OEM (3x10 users) 2,51,000 - - - 2,51,000

5 Microsoft Office Home & business 2010 Full pack

(30 users) 2,81,910 - - - 2,81,910

6 Adobe suite master collection version 6 (30 users) 20,35,020 - - - 20,35,020

7 Kaspersky antivirus business pack 30 user 27, 783 27, 783 27, 783 27, 783 1,11,132

8 Navicat Premium (4 users) 73, 920 - - - 73, 920

TOTAL 82,19,633 85,77,783 55,77,783 85,77,783 3,09,52,982

Sub-Total (B.2) =Rs. 3,09,52,982/-

Justification:

1. Conferences- will be organized on the second and fourth years of this project. A set of 10 world leaders in signal transduction who have

significantly contributed to the field of signal transduction will be invited for lectures. The students and the faculty members from the

Participating Centres; and the scientists from Institute of Bioinformatics will attend these conferences. The pathways developed and those which

are under development during the span of 1-2 years will be presented in these conferences for effective interaction on specific signaling

61

pathways and also to seek future directions on pathway development and analysis. In the second conference, the prime focus will be on the

global perspectives to pathway data analysis with the active participation of the bioinformatics community in India.

2. Open access charges for publications- Currently, 5 individual pathways developed at IOB with the participation of Participating Institutes

(viz: RANKL pathway with Armed Forces Medical College, Leptin pathway with Amrita Viswa Vidypeedm, FSH pathway with National

Institute for Research in Reproductive Health, and TSH & TWEAK pathways with Pondicherry University) had been published in international

journals (Raju et al., 2011, Nanjappa et l., 2011, Telikicherla et al., 2011, Goel et al., 2011 and Bhattacharjee et al, 2012). With the involvement

of large number of students (around 130 students per year) and focused effort of individual students supported by the faculty scientists, 2

Research associates and 10 Senior Research Fellows from IOB and Project Leaders from the Participating Institutes, there will be over 100

pathway manuscripts ready for publication in international journals per year. With ~US$1000 (Rs. 55,000/-) on the average as the amount for

publication, this amounts to Rs. 55,00,000/-. For example, publication charges of the research articles already published are provided in table

below:

Journal Publishers Pathway published Reference Article processing charge

1 Database Oxford University

Press RANKL signaling pathway Raju et al., 2011 US$1600

2 BMC Research Notes BioMed Central Follicle Stimulating Hormone

signaling pathway Telikicherla et al., 2011 US$1090

3 Journal of Proteomics

and Bioinformatics

OMICS Publishing

Group Leptin signaling pathway Nanjappa et al., 2011 US$1300

4 Journal of Proteomics

and Bioinformatics

OMICS Publishing

Group

Thyroid Stimulating Hormone

signaling pathway Goel et al., 2011 US$700

5 Journal of Signal

Transduction

Hindawi Publishing

Corporation

TWEAK-Fn14

signaling pathway Bhattacharjee et al, 2012 US$500

3. Partial internet charges- The development of signaling pathways requires high-speed internet to access research articles, PathBuilder tool for

documentation of pathway data, training, and remote monitoring of pathway development.

4. Microsoft Windows 7 Pro 32 bit OEM- is required for the basic graphical user interface.

Microsoft Office Home & business 2010 Full pack- is required for documentation, pathway curation, editing, and manuscript preparation

62

5. Kaspersky antivirus business pack - is essential for the anti-virus support to safeguard the pathway information obtained by the rigorous

manual work

6. Adobe suite master collection version 6- is required to generate signaling pathway data, development of high-quality pathway images, and

also for the manuscript preparation.

7. Navicat premium- Navicat Premium is a multi-connections Database Administration tool which allows to connect to MySQL, SQL Server,

SQLite, Oracle and PostgreSQL databases simultaneously within a single application. This facilitates better database administration to multiple

kinds of databases associated with NetPath and NetSlim.

5. Travel

Item Year 1 Year 2 Year 3 Year 4 Total (INR)

B.3 Travel 5,00,000 5,00,000 5,00,000 5,00,000 20,00,000

B.4 Contingency 2,00,000 2,00,000 2,00,000 2,00,000 8,00,000

Total 7,00,000 7,00,000 7,00,000 7,00,000 28,00,000

Justification:

1. Travel- This includes the travel expenses of the Principal Investigator, Co- Principal Investigators, Research Associates, and Senior Research

Fellows to the Participating Institutes for the orientation, workshops and hands-on training programmes. The faculty scientists, RAs and JRFs

will also visit the Participating Institutes to improve the curation quality after their review of pathway curation made by the students.

Sub-Total (B = B.1 + B.2 + B.3 + B.4) = Rs. 7,04,90,582/-

Grand Total (A + B) = Rs. 7,54,95,802/-

63

University of Pune A. Non-Recurring: None B. Recurring B1. Manpower


allowances Year 1 Year 2 Year 3 Year 4 Total

1 Trainees

(5 per year) Rs. 10,000/-

(Onetime payment for 60 days) 50,000 50,000 50,000 50,000 2,00,000

Total 50,000 50,000 50,000 50,000 2,00,000

Sub-Total (B.1) = Rs. 2,00,000/- Justification: In addition to the trainees selected and funded by IOB (nodal center), University of Pune can also fund 5 trainees, who may not opt for travelling to IOB. These trainees will be trained locally by the project leaders in University of Pune. IOB Senior Research Fellows and Investigators will remotely monitor the training. This opportunity will help several female students, who may have special circumstances, which may not allow their 60 days visit to IOB, the nodal center of this program. Selected trainees will participate in this project during their semester breaks and summer vacations. B.2 Consumables

Item Year 1 Year 2 Year 3 Year 4 Total Partial internet charges 25,000 25,000 25,000 25,000 1,00,000 Software (Adobe and Windows related) 2,00,000 - - - 2,00,000 TOTAL 2,25,000 25,000 25,000 25,000 3,00,000

Sub-Total (B.2) =Rs. 3,00,000/-

Item Year 1 Year 2 Year 3 Year 4 Total

B.3 Travel 30,000 30,000 30,000 30,000 1,20,000

B.4 Contingency 50,000 50,000 50,000 50,000 2,00,000

B.5 Overhead Charges (15% of recurring) 53,250 23,250 23,250 23,250 123,000 Sub-Total (B = B.1 + B.2 + B.3 + B.4 + B.5) = Rs. 9,43,000/- Grand Total (A + B) = Rs. 9,43,000/-

64

Pondicherry University A. Non-Recurring: None B. Recurring B1. Manpower



1 Trainees

(5 per year) Rs. 10,000/-


Total 50,000 50,000 50,000 50,000 2,00,000

Sub-Total (B.1) = Rs. 2,00,000/- Justification: In addition to the trainees selected and funded by IOB (nodal center), Pondicherry University can also fund 5 trainees, who may not opt for travelling to IOB. These trainees will be trained locally by the project leaders in Pondicherry University. IOB Senior Research Fellows and Investigators will remotely monitor the training. This opportunity will help several female students, who may have specia l circumstances, which may not allow their 60 days visit to IOB, the nodal center of this program. Selected trainees will participate in this project during their semester breaks and summer vacations. B.2 Consumables


Sub-Total (B.2) =Rs. 3,00,000/-


B.3 Travel 30,000 30,000 30,000 30,000 1,20,000

B.4 Contingency 50,000 50,000 50,000 50,000 2,00,000


65

Madurai Kamaraj University A. Non-Recurring: None B. Recurring B1. Manpower



1 Trainees

(5 per year) Rs. 10,000/-


Total 50,000 50,000 50,000 50,000 2,00,000

Sub-Total (B.1) = Rs. 2,00,000/- Justification: In addition to the trainees selected and funded by IOB (nodal center), Madurai Kamaraj University can also fund 5 trainees, who may not opt for travelling to IOB. These trainees will be trained locally by the project leaders in Madurai Kamaraj University. IOB Senior Research Fellows and Investigators will remotely monitor the training. This opportunity will help several female students, who may have specia l circumstances, which may not allow their 60 days visit to IOB, the nodal center of this program. Selected trainees will participate in this project during their semester breaks and summer vacations. B.2 Consumables


Sub-Total (B.2) =Rs. 3,00,000/-


B.3 Travel 30,000 30,000 30,000 30,000 1,20,000

B.4 Contingency 50,000 50,000 50,000 50,000 2,00,000


66

University of Mysore A. Non-Recurring: None B. Recurring B1. Manpower



1 Trainees

(5 per year) Rs. 10,000/-


Total 50,000 50,000 50,000 50,000 2,00,000

Sub-Total (B.1) = Rs. 2,00,000/- Justification: In addition to the trainees selected and funded by IOB (nodal center), University of Mysore can also fund 5 trainees, who may not opt for travelling to IOB. These trainees will be trained locally by the project leaders in University of Mysore. IOB Senior Research Fellows and Investigators will remotely monitor the training. This opportunity will help several female students, who may have special circumstances, which may not allow their 60 days visit to IOB, the nodal center of this program. Selected trainees will participate in this project during their semester breaks and summer vacations. B.2 Consumables


Sub-Total (B.2) =Rs. 3,00,000/-


B.3 Travel 30,000 30,000 30,000 30,000 1,20,000

B.4 Contingency 50,000 50,000 50,000 50,000 2,00,000


67

Kuvempu University A. Non-Recurring: None B. Recurring B1. Manpower



1 Trainees

(5 per year) Rs. 10,000/-


Total 50,000 50,000 50,000 50,000 2,00,000

Sub-Total (B.1) = Rs. 2,00,000/- Justification: In addition to the trainees selected and funded by IOB (nodal center), Kuvempu University can also fund 5 trainees, who may not opt for travelling to IOB. These trainees will be trained locally by the project leaders in Kuvempu University. IOB Senior Research Fellows and Investigators will remotely monitor the training. This opportunity will help several female students, who may have special circumstances, which may not allow their 60 days visit to IOB, the nodal center of this program. Selected trainees will participate in this project during their semester breaks and summer vacations. B.2 Consumables


Sub-Total (B.2) =Rs. 3,00,000/-


B.3 Travel 30,000 30,000 30,000 30,000 1,20,000

B.4 Contingency 50,000 50,000 50,000 50,000 2,00,000


68

Mangalore University A. Non-Recurring: None B. Recurring B1. Manpower



1 Trainees

(5 per year) Rs. 10,000/-


Total 50,000 50,000 50,000 50,000 2,00,000

Sub-Total (B.1) = Rs. 2,00,000/- Justification: In addition to the trainees selected and funded by IOB (nodal center), Mangalore University can also fund 5 trainees, who may not opt for travelling to IOB. These trainees will be trained locally by the project leaders in Mangalore University. IOB Senior Research Fellows and Investigators will remotely monitor the training. This opportunity will help several female students, who may have special circumstances, which may not allow their 60 days visit to IOB, the nodal center of this program. Selected trainees will participate in this project during their semester breaks and summer vacations. B.2 Consumables


Sub-Total (B.2) =Rs. 3,00,000/-


B.3 Travel 30,000 30,000 30,000 30,000 1,20,000

B.4 Contingency 50,000 50,000 50,000 50,000 2,00,000


69

Central University of Kerala A. Non-Recurring: None B. Recurring B1. Manpower



1 Trainees

(5 per year) Rs. 10,000/-


Total 50,000 50,000 50,000 50,000 2,00,000

Sub-Total (B.1) = Rs. 2,00,000/- Justification: In addition to the trainees selected and funded by IOB (nodal center), Central University of Kerala can also fund 5 trainees, who may not opt for travelling to IOB. These trainees will be trained locally by the project leaders in Central University of Kerala. IOB Senior Research Fellows and Investigators will remotely monitor the training. This opportunity will help several female students, who may have specia l circumstances, which may not allow their 60 days visit to IOB, the nodal center of this program. Selected trainees will participate in this project during their semester breaks and summer vacations. B.2 Consumables


Sub-Total (B.2) =Rs. 3,00,000/-


B.3 Travel 30,000 30,000 30,000 30,000 1,20,000

B.4 Contingency 50,000 50,000 50,000 50,000 2,00,000


70

University of Kerala A. Non-Recurring: None B. Recurring B1. Manpower



1 Trainees

(5 per year) Rs. 10,000/-


Total 50,000 50,000 50,000 50,000 2,00,000

Sub-Total (B.1) = Rs. 2,00,000/- Justification: In addition to the trainees selected and funded by IOB (nodal center), University of Kerala can also fund 5 trainees, who may not opt for travelling to IOB. These trainees will be trained locally by the project leaders in University of Kerala. IOB Senior Research Fellows and Investigators will remotely monitor the training. This opportunity will help several female students, who may have special circumstances, which may not allow their 60 days visit to IOB, the nodal center of this program. Selected trainees will participate in this project during their semester breaks and summer vacations. B.2 Consumables


Sub-Total (B.2) =Rs. 3,00,000/-


B.3 Travel 30,000 30,000 30,000 30,000 1,20,000

B.4 Contingency 50,000 50,000 50,000 50,000 2,00,000


71

Anna University A. Non-Recurring: None B. Recurring B1. Manpower



1 Trainees

(5 per year) Rs. 10,000/-


Total 50,000 50,000 50,000 50,000 2,00,000

Sub-Total (B.1) = Rs. 2,00,000/- Justification: In addition to the trainees selected and funded by IOB (nodal center), Anna University can also fund 5 trainees, who may not opt for travelling to IOB. These trainees will be trained locally by the project leaders in Anna University. IOB Senior Research Fellows and Investigators will remotely monitor the training. This opportunity will help several female students, who may have special circumstances, which may not allow their 60 days visit to IOB, the nodal center of this program. Selected trainees will participate in this project during their semester breaks and summer vacations. B.2 Consumables


Sub-Total (B.2) =Rs. 3,00,000/-


B.3 Travel 30,000 30,000 30,000 30,000 1,20,000

B.4 Contingency 50,000 50,000 50,000 50,000 2,00,000


72

Armed Forces Medical College A. Non-Recurring: None B. Recurring B1. Manpower



1 Trainees

(5 per year) Rs. 10,000/-


Total 50,000 50,000 50,000 50,000 2,00,000

Sub-Total (B.1) = Rs. 2,00,000/- Justification: In addition to the trainees selected and funded by IOB (nodal center), Armed Forces Medical College can also fund 5 trainees, who may not opt for travelling to IOB. These trainees will be trained locally by the project leaders in Armed Forces Medical College. IOB Senior Research Fellows and Investigators will remotely monitor the training. This opportunity will help several female students, who may have special circumstances, which may not allow their 60 days visit to IOB, the nodal center of this program. Selected trainees will participate in this project during their semester breaks and summer vacations. B.2 Consumables


Sub-Total (B.2) =Rs. 3,00,000/-


B.3 Travel 30,000 30,000 30,000 30,000 1,20,000

B.4 Contingency 50,000 50,000 50,000 50,000 2,00,000


73

PART V: EXISTING FACILITIES

21. Available equipment and accessories to be utilized for the project:

S.

No.

Name of

equipment

/Accessories

Make Model

1

Sun Server Sun Sun Fire V60x Sun Fire CGM

2 PCs x 40

(Occupied)

256 MB Ram, AMD Athlon

XP 2GHz Processor, 40 GB

hard disk

-

3 LCD projector Toshiba TLP-B2UltraSU

4. Server Sun Sun Fire X4450, Sun Fire X4150

6 Ink jet printers Hewlett Packard -

7 Scanner Canon -