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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.