Date of Award
Doctor of Philosophy (PhD)
Cardiac fibrosis poses a central challenge in preventing heart failure for patients who have suffered a cardiac injury such as myocardial infarction or aortic valve stenosis. This chronic condition is characterized by a reduction in contractile function through combined hypertrophy and excessive scar formation, and although currently prescribed therapeutics targeting hypertrophy have shown improvements in patient outcomes, pathological fibrosis remains a leading cause of reduced cardiac function for patients long-term. Cardiac fibroblasts play a key role in regulating scar formation during heart failure progression, and interacting biochemical and biomechanical cues within the myocardium guide the activation of fibroblasts and expression of extracellular matrix proteins. While targeted experimental studies of fibroblast activation have elucidated the roles of individual pathways in fibroblast activation, intracellular crosstalk between mechanotransduction and chemotransduction pathways from multiple biochemical cues has largely confounded efforts to control overall cell behavior within the myocardial environment.
Computational networks of intracellular signaling can account for complex interactions between signaling pathways and provide a promising approach for identifying influential mechanisms mediating cell behavior. The overarching goal of this dissertation is to improve our understanding of complex signaling in fibroblasts by investigating the role of mechano-chemo interactions in cardiac fibroblast-mediated fibrosis using a combination of experimental studies and systems-level computational models. Firstly, using an in vitro screen of cardiac fibroblast-secreted proteins in response to combinations of biochemical stimuli and mechanical tension, we found that tension modulated cell sensitivity towards biochemical stimuli, thereby altering cell behavior based on the mechanical context. Secondly, using a curated model of fibroblast intracellular signaling, we expanded model topology to include robust mechanotransduction pathways, improved accuracy of model predictions compared to independent experimental studies, and identified mechanically dependent mechanisms-of- ction and mechano-adaptive drug candidates in a post-infarction scenario. Lastly, using an inferred network of fibroblast transcriptional regulation and model fitting to patient-specific data, we showed the utility of model-based approaches in identifying influential pathways underlying fibrotic protein expression during aortic valve stenosis and predicting patient-specific responses to pharmacological intervention. Our work suggests that computational-based approaches can generate insight into influential mechanisms among complex systems, and such tools may be promising for further therapeutic development and precision medicine.
Rogers, Jesse Daniel, "Systems Modeling to Predict Mechano-Chemo Interactions In Cardiac Fibrosis" (2021). All Dissertations. 2795.