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Dissertation Defense Announcement
To:  The George Mason University Community

Candidate: Sarita Limbu

Program: PhD in Bioinformatics & Computational Biology



Date:   Wednesday July 27, 2016

Time:   11:00 AM
Place:  George Mason University
             Science & Tech (Prince William) Campus<http://www.gmu.edu/resources/welcome/Directions-to-GMU.html>
            Colgan Hall (Occoquan Bldg.), Room 204



Title: "Predicting the Effects of Stretch-Activated Reactive Oxygen Species Signaling on Cardiac Excitation-Contraction Coupling"
Committee Chair: Dr. M. Saleet Jafri

Committee Members:  Dr. Dmitri Klimov, Dr. Patrick Gillevet

A copy of the dissertation is available in the Gateway Library.  All are invited to attend the defense.
ABSTRACT:
Calcium (Ca2+) is an important second messenger in cardiac myocytes and regulates the excitation-contraction (EC) coupling, the process which converts electrical signal into the mechanical contraction of the myocytes.  Regulation of the Ca2+ released from sarcoplasmic reticulum (SR), the Ca2+ store in cardiac myocytes, via ryanodine receptor 2 (RyR2), the Ca2+ release channel in the SR, is crucial for physiological functioning of the myocyte. Reactive oxygen species (ROS) regulate cardiac Ca2+ signaling by oxidizing and increasing the open probability of RyR2s. Stretching of a cardiac myocyte has been shown to induce Nox2 mediated ROS production in a process termed X-ROS signaling that abruptly increases the Ca2+ released from the SR. A computational model of the rat cardiac ventricular myocyte with X-ROS signaling was developed. The model was used to investigate the underlying mechanisms of regulation of EC coupling by X-ROS. The X-ROS dependent effects of oxidative stress on EC coupling during pathology, such as heart failure, were studied. Stretching a cardiomyocyte elevates the intracellular Ca2+ concentration via X-ROS but on the other hand, the increase in affinity of troponin for Ca2+ increases the Ca2+ buffering and decreases the free cytosolic Ca2+ concentration. The X-ROS mediated effects of length dependent change in Ca2+ binding affinity of troponin and its subsequent effects on Ca2+ dynamics were also studied. The model was integrated into the spatial model and the spatial model of a ventricular myocyte model with X-ROS signaling was developed to understand various spatial components which would contribute towards abnormalities such as arrhythmia during pathologies.

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