Junctophilin-2 in Cardiac Fibroblasts - PROJECT SUMMARY / ABSTRACT Cardiac fibrosis is a wound healing response to heart injury that plays a critical role in structural and electrical remodeling of the heart. It is a common feature in most heart diseases, particularly following ischemic events like myocardial infarction (MI). Cardiac fibroblasts (CFs), the prominent nonmyocyte population in heart tissue, are important for maintaining normal cardiac function, facilitating wound healing, and mediating remodeling after injury. CFs proliferate and migrate to the affected areas, where they deposit excess extracellular matrix proteins to aid in tissue repair. Calcium (Ca2+) signaling is pivotal in regulating key aspects of fibroblast biology, including migration, differentiation, and gene expression. However, the mechanisms that establish Ca2+ homeostasis in CFs and their role in cardiac fibrotic remodeling remain poorly understood. In pilot studies, we found, Junctophilin-2 (JP2), a structural protein crucial for organizing the junctional couplings between the T-tubule plasma membrane and the sarcoplasmic reticulum (SR) in cardiomyocytes, is uniquely expressed in CFs and is vital for maintaining their Ca2+ homeostasis. Further work suggests that JP2 deficiency in CFs impairs scar formation and exacerbates heart function after MI, likely due to impaired Ca2+ regulation. Based on these preliminary findings, we hypothesize that JP2-mediated Ca2+ signaling is essential for CF responses to ischemic challenges and that defects in this signaling pathway contribute to aberrant fibrotic remodeling following injury. This project will employ advanced molecular, physiological, and biochemical techniques, along with innovative mouse models, to investigate the specific mechanisms through which JP2 influences CFs and its role in injury- induced cardiac fibrosis. The anticipated outcomes of this research include providing novel knowledge on JP2's physiological and pathophysiological functions in CFs, shedding light on the mechanisms driving cardiac fibrosis and heart dysfunction after injury. Ultimately, these insights may pave the way for the development of new treatments targeting cardiac fibrotic process and improving heart health outcomes.
