Modeling Nuclear and Intracellular Calcium ynamics in Rabbit Ventricular Cardiomyocytes KyleDavid Lim Suico University of Queensland July 30 2014 UCSD PRIME
Modeling Nuclear and Intracellular Calcium Dynamics in Rabbit Ventricular Cardiomyocytes
Kyle-‐David Lim Suico University of Queensland
July 30 2014 UCSD PRIME
Using the Nimrod toolkit, a set of tools that allows for inves6ga6ng highly complicated parametric systems, my goal is to op6mize Excita6on-‐Contrac6on-‐Transcrip6on-‐Coupling Model (Shannon-‐Bers-‐Michailova Model) for a ventricular cardiomyocyte in rabbits and run sensi6vity analysis in order to elucidate how the model behaves under various s6muli.
The model will be op6mized and fiIed for 4 kine6c measurements of calcium:
§ Systolic (mM) § Diastolic (mM) § Time-‐to-‐peak (ms) § Res6ng 6me to 50% peak calcium concentra6on (ms)
Research Proposal
Hohendanner et al., 2014
Experimental Simulated LeR: Schema6c for a ventricular cardiomyocyte. Right: Experimental calcium vs. simulated data from MATLAB, Both plots show calcium vs. 6me (non-‐dimensionalized).
Progress: Nimrod/E & PLS Tool Results Figure: Results from a ±10% perturba6on in nucleus parameter values. The leR column of plots are the Lenth plots from Nimrod /E and to the right are the corresponding PLS regression plots explaining the correla6on.
Le*: Nimrod/E’s Lenth Plot. Top plot corresponds to 6me to peak and boIom corresponds to res6ng 6me to 50% calcium measurement.
Right: Results from the PLS Tool. Variables going from leR to right correspond to (A-‐K). Note there is no variable “I’.
Parameters A & B are directly correlated with 6me and create a “lag” in the calcium transient.
Parameters C, D, & E are indirectly correlated with the 6me kine6c parameters.
Progress: Nimrod/E & PLS Tool Results
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Figure: Results from a ±10% perturba6on in nucleus parameter values. The leR column of plots are the Lenth plots from Nimrod /E and to the right are the corresponding PLS regression plots explaining the correla6on.
Le*: Nimrod/E’s Lenth Plot. Top plot corresponds to systolic calcium and the boIom corresponds to the diastolic calcium measurement.
Right: Results from the PLS Tool. Variables going from leR to right correspond to (A-‐K). Note there is no variable “I’.
Parameter G has a rela6vely strong correla6on with systolic and diastolic calcium measurements.
Parameter H has an rela6vely strong indirect correla6on with both systolic and diastolic calcium measurements.
ReflecQon Slide
Road blocks: Experienced problems quan6fying rela6onship and the degree of correla6on between key parameters. Encountered issues with fibng experimental data. Issues es6ma6ng parameter values.
Successes:
Learned how to use PLS regression tool and make corresponding plots to Nimrod/E data. Cleaned up data analysis methods -‐ reducing varia6on across samples allowing for accurate fits. Refined op6miza6on script, crea6ng 4 addi6onal versions serving different purposes.
Future Plans
• Extract more kine6c parameter data from experimental data and calculate popula6on sta6s6cs.
• Carry out parameter es6ma6on using experimental data. • Conduct sensi6vity analysis by perturbing parameters in the nucleus by ±10, 30, 50, and 100%.
• Iden6fy mechanisms that contribute to nuclear Ca2+ transport.
Surfer’s Paradise, Gold Coast Le* most: Relaxing with some live music at SkyPoint’s Lounge. Top Le*: Welcoming sign to the beach. Top Right: View of the Gold Coast from the SkyPoint tower from the 77th floor! Bo4om Le*: Group selfie! Bo4om Right: Beau6ful night view from the Skypoint tower.
Acknowledgements
University of California, San Diego ● Dr. McCulloch, Department of Bioengineering ● Dr. Sukri6 Dewan and BriIon Boras ● UCSD PRIME -‐ Dr. Gabriele Wienhausen and Ms. Teri Simas
University of Queensland ● Dr. David Abramson, Centre of Research Compu6ng ● Timos Kipouros and Blair Bethwaite ● Minh Dinh, Hoang Nguyen, and Minh Huynh
Funding by: Revelli Family Scholarship Prime Alumna Haley-‐Hunter Zinck Na6onal Science Founda6on
R.I.P. Dr. Anushka Michailova In memory of Dr. Michailova… a mother, mentor, and scien6st.