William Richardson, Ph.D.
Assistant Professor of Bioengineering
Roughly 1 million Americans suffer a myocardial infarction (MI) each year, after which necrotic myocardium is replaced by collagen, deposited by fibroblasts in response to chemical and mechanical cues. Post-MI, accumulation of collagen within the infarct scar is critical to prevent scar expansion and rupture, but excessive collagen can be detrimental to regenerating myocytes. As a novel approach for reducing collagen content only when and where it is safe to do so, we propose that local stretch can provide self-adapting feedback to modulate collagen signaling and thereby enable self-adjusting specificity for anti-fibrotic therapy. The long-term objective of this project is to employ a computational model of cardiac fibroblast signaling alongside in vitro validation experiments in order to identify perturbations that reduce collagen in regions of low stretch (e.g., regenerating myocardium), but maintain collagen in regions of high stretch (e.g., infarct scar). We and collaborators have recently published a large-scale signaling network model of intracellular signal transduction that predicts fibrosis-related synthesis outputs (matrix, proteases, and protease inhibitors) given both mechanical and biochemical stimuli (e.g., growth factors, hormones, etc.). In this pilot proposal, we aim to (1) conduct in vitro cell-stretching experiments to test the model-predicted hypothesis that stretch can sensitize, de-sensitize, or even reverse cell synthesis responses to biochemical stimuli, and (2) to refine model parameters to match experimental data. This pilot project will produce a well-validated, large-scale model that we will immediately use in a follow-up project to conduct computational pharmacologic screens that identify drug strategies to provide the desirable mechano-adaptive fibrosis therapy: decreased collagen for improved infarct regeneration strategies while maintaining adequate levels of collagen in scar tissue.