Project Summary The goal of this K08 application is to provide a rigorous 5-year scientific and career development training plan that will facilitate the transition of Dr. Glynnis Garry from a post-doctoral fellow to a fully independent investigator as a cardiovascular physician-scientist. Dr. Garry obtained her medical degree from Vanderbilt University during which she pursued a rigorous and productive 1.5 year molecular biology training through a Sarnoff Cardiovascular Research Fellowship at UT Southwestern in the laboratory of Eric Olson, Ph.D, one of the world’s leading experts in muscle biology and cardiovascular regeneration. After completing a short-tracked Internal Medicine residency at UT Southwestern through the Physician-Scientist Training Program, Dr. Garry joined the laboratory of Dr. Olson as a post-doctoral fellow, where she directed her focus to investigating direct cardiac reprogramming as a means of promoting heart regeneration following myocardial infarction. Reprogramming of fibroblasts to cardiomyocytes has emerged as an attractive strategy to redirect the fibrotic response of the injured, non-regenerative heart toward a functional myocardium. However, previously discovered cocktails have been ineffective in reprogramming adult human fibroblasts, limiting the clinical application of this strategy. From a large unbiased screen, Dr. Garry identified the histone reader PHF7 as the most potent activator of adult reprogramming. Her preliminary work demonstrated the ability of PHF7 to markedly activate reprogramming in adult human and mouse fibroblasts by increasing chromatin accessibility at cardiac super enhancers when added to a five-factor reprogramming cocktail. She also discovered the ability of PHF7 to activate adult murine reprogramming in the absence of canonical reprogramming factors. Further, she recently generated data demonstrating the ability of PHF7 to improve cardiac function following myocardial infarction, which is an unprecedented result that merits further characterization. In her proposed research, Dr. Garry under the mentorship of Dr. Olson will aim to 1) define the role of PHF7 in adult human reprogramming, 2) define the ability of PHF7 and PHF7 cocktails to improve cardiac function following myocardial infarction, and 3) delineate mechanisms by which PHF7 induces reprogramming events and improvement in cardiac function in vivo. These studies will potentially provide the basis for development of a novel therapeutic factor for the treatment of ischemic heart disease and advance our understanding of mechanisms that drive reprogramming. Dr. Olson is a pioneer in the field of cardiac reprogramming with a storied legacy of mentorship. He is fully committed to mentoring the career of Dr. Garry, and together they have assembled an outstanding advisory committee to ensure her success through scientific mentorship, grantsmanship, coursework, and career development opportunities. Given her outstanding mentorship, produ...