Regulation of Cardiac Fibrosis in Heart Failure by the Cytokine FAM3D

PROJECT SUMMARY / ABSTRACT: Heart failure (HF) is a major public health concern with increasing prevalence in the United States and globally, particularly in the elderly, for whom it represents the leading cause of hospitalization. While dysregulated inflammation, cardiac fibrosis, and neurohormonal activation are observed in the maladaptive remodeling of HF, the precise molecular mechanisms that underlie these cellular phenomena are incompletely understood. Interestingly, the salutary effects of exercise have been shown to slow or even reverse the functional decline of HF both in humans and in animal models. This research proposal outlines a 2-year plan for the Principal Investigator, Dr. James Rhee, M.D., Ph.D., Director of Neuroanesthesia at Massachusetts General Hospital (MGH) and Assistant Professor at Harvard Medical School (HMS), to lead a team of expert scientists in studying the role of the cytokine Family with sequence similarity 3 member D (FAM3D) in heart failure. Dr. Rhee has previously identified FAM3D as highly upregulated in the plasma of patients who experienced favorable cardiac remodeling and restoration of function after heart attack. In animal models of cardiac ischemia reperfusion injury, FAM3D overexpression limited infarct size by suppressing inflammatory cell trafficking into the damaged myocardium. Presented in this current proposal are compelling data showing that FAM3D directly regulates cardiofibroblast activation. Its anti- inflammatory and anti-fibrotic roles overlap with those observed in the hearts of exercise-trained mice. Given its constellation of effects on immune cells and fibroblasts in limiting injury and promoting recovery, FAM3D likely possesses multifactorial benefits in curtailing the progression of HF. Dr. Rhee and his team will rigorously interrogate how this cytokine governs non-immune cells in the heart, namely fibroblasts and lymphatic endothelial cells. They will carefully assess how gain or loss of FAM3D affects cardiac function in two widely used animal models of HF, namely that of pressure overload (Aim 1) and aging (Aim 2), and any requirement for TGF-3 as a downstream signal. The research team will also manipulate FAM3D in the aging heart in the setting of exercise. There will be special emphasis placed on the characterization of the cardiac lymphatic system, which has received increasing attention as an integral component of myocardial health and is intimately tied to both inflammation and fibrosis. The approach herein combines innovative hypotheses, unique technologies and animal models, and collaborating investigators who possess highly specialized skillsets. Completion of these studies will provide valuable insight into the pathogenesis of HF, and lead to the identification of promising new therapeutic targets.