Mechanotransduction Mechanisms of Cardiac Growth and Regeneration

Project Summary More than a million Americans experience a heart attack each year causing irreversible damage to their heart muscle. Current therapies prolong survival by protecting remaining cardiomyocytes but are unable to overcome the fundamental problem of replacing lost cardiomyocytes. Thus, understanding which molecular pathways govern cardiomyocyte proliferation is a high priority in the effort to explore new treatments for heart failure. The transition from hyperplastic to hypertrophic growth in the postnatal heart is accompanied by dynamic remodeling of cell-cell and cell-extracellular matrix (ECM) adhesion structures, suggesting that cell adhesion/cytoskeletal changes play a critical role in myocardial growth control. In support of this idea our lab found that modifying the connection between N-cadherin and the actin cytoskeleton leads to accumulation of Yap in the nucleus, increase cardiomyocyte proliferation, and improved cardiac function following myocardial infarction in mice. The overall goal of this new project is to elucidate the molecular mechanisms regulating the dynamic nature and interplay between myocardial cell-cell and cell-ECM interactions and the ensuing downstream signals that ultimately control cardiomyocyte proliferation. Aim 1 will determine the requirement for post-translational modification of a cytoskeletal adaptor protein in junction maturation, cardiomyocyte differentiation and cell cycle arrest in the neonatal heart, Aim 2 will determine whether inhibiting phosphorylation of this cytoskeletal adaptor protein, either genetically or pharmacologically, will promote heart muscle regeneration following myocardial infarction, and Aim 3 will elucidate mechanical consequences of altering VCL function in human iPSC-derived cardiomyocytes. Completion of these preclinical proof-of-concept studies will determine whether targeting cell adhesion/cytoskeletal linkage represents a novel strategy to stimulate cardiomyocyte proliferation following ischemic injury.