Systems Biology Approaches Identify Mechanisms of Inter- and Intracellular Communication in Heart Disease

Author: ORCID icon
Chowkwale, Mukti Subhash, Biomedical Engineering - School of Engineering and Applied Science, University of Virginia
Saucerman, Jeffrey, MD-BIOM Biomedical Eng, University of Virginia

Myocardial infarction (MI) is the most common cause of heart failure. During an MI, up to 1 billion cardiac cells die in response to ischemia. This cell death leads to the activation of fibroblasts and immune cells. The adult human heart has a limited capacity to regenerate, thus the dead cells are cleared and replaced by a scar. This is followed by remodeling in the surrounding myocardium, which includes thickening and stiffening of the left ventricular wall. Both of these newly acquired characteristics eventually lead to impaired cardiac function. The overarching goal of this dissertation is to predict and identify novel signaling mechanisms within and between cardiac cells that regulate cardiac fibrosis post myocardial infarction. In Aim 1, I develop and apply an intercellular, computational model of the healing infarct to delineate mechanisms of inflammation-fibrosis coupling post-MI. In Aim 2, I couple single-cell RNA-sequencing data and network modeling to predict and validate novel pro-proliferative ligands of cardiac fibroblasts. Aim 3 explores methods to identify regulators of sex dimorphism in cardiac fibroblasts using network modeling. Thus, this work identifies novel signaling mechanisms in the healing infarct.

PHD (Doctor of Philosophy)
systems biology, cardiac fibrosis
Sponsoring Agency:
American Heart AssociationNational Institutes of HealthUVA School of Engineering and Applied Science
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