Systems Biology of Fibroblast Activation Following Myocardial Infarction

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 DESCRIPTION (provided by applicant): About one in four myocardial infarction (MI) patients progress to develop congestive heart failure, which has a 50% 5-year mortality rate. The goal of this project is to understand post-MI roles of the fibroblast by establishing and validating an in silico computational model of the temporal evolution of fibroblast activation. Our preliminary results demonstrate that fibroblasts proceed through a series of activation profiles over the first 28 days post-MI and that modifying fibroblast responses can alter remodeling of the left ventricle (LV). We hypothesize that fibroblasts undergo a temporal phenotype evolution to coordinate the post-MI LV remodeling phenotype. Our specific aims are: 1) construct an in silico computational model that simulates fibroblast activation patterns over the post-MI time course; 2) Perturb endogenous cytokine and growth factor signaling pathways to evaluate the system and optimize model robustness.; and 3) Examine endogenous ECM influences to evaluate model predictability. The innovation of this proposal lies in both the concept that fibroblasts regulate remodeling as a continuum of phenotypes and that integration of experimental and computational approaches will allow us to establish a predictive computational tool. The potential outcome of these studies will be 1) the development of a computational tool to simulate fibroblast activation post-MI; 2) the identification of fibroblast activation markers that predict V remodeling outcomes; and 3) recognition of key fibrotic mechanisms that can be therapeutically modulated to regulate fibroblast activation.