Predicting the Effects of Stretch-Activated Reactive Oxygen Species Signaling on Cardiac Excitation-Contraction Coupling
| dc.contributor.advisor | Jafri, Mohsin S | |
| dc.contributor.author | Limbu, Sarita | |
| dc.creator | Limbu, Sarita | |
| dc.date.accessioned | 2017-01-29T01:16:35Z | |
| dc.date.available | 2017-01-29T01:16:35Z | |
| dc.date.issued | 2016 | |
| dc.description.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. | |
| dc.format.extent | 127 pages | |
| dc.identifier.uri | https://hdl.handle.net/1920/10591 | |
| dc.language.iso | en | |
| dc.rights | Copyright 2016 Sarita Limbu | |
| dc.subject | Bioinformatics | |
| dc.subject | Calcium | |
| dc.subject | Cardiac | |
| dc.subject | ROS | |
| dc.subject | Stretch | |
| dc.title | Predicting the Effects of Stretch-Activated Reactive Oxygen Species Signaling on Cardiac Excitation-Contraction Coupling | |
| dc.type | Dissertation | |
| thesis.degree.discipline | Bioinformatics and Computational Biology | |
| thesis.degree.grantor | George Mason University | |
| thesis.degree.level | Ph.D. |
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