BRD4, a Crucial Positive Regulator of Aging-Associated Diastolic Dysfunction

点击翻译按钮获取中文摘要

Project Summary Dr. Stratton, a Research Assistant Professor in the Dept. of Physiology and Cell Biology at The Ohio State University (OSU) Wexner Medical Center, proposes to investigate the role of an epigenetic reader protein, BRD4, in aging-associated heart failure. Dr. Stratton has previously held an individual NIH NRSA Postdoctoral Fellowship and has a strong publication record from his graduate and postdoctoral training and is committed to a career as an academic research leader. The proposal is for a Mentored Research Scientist Development (K01) award to help facilitate a transition to research independence. The research environment at OSU is very strong in both clinical and basic research. Dr. Stratton has assembled a strong team of mentors and collaborators to help ensure success of the proposed experiments and the maturation of Dr. Stratton into a successful independent investigator. His primary mentor will be Dr. Peter Mohler, Chair Dept. of Physiology and Cell Biology, and Vice Dean for Research OSU College of Medicine. Dr. Timothy McKinsey, Associate Professor and Assistant Department Head for Translation and Director of CFReT at UC Denver will serve as a formal co- mentor, and was Dr. Stratton's postdoctoral advisor. Members of the mentoring committee include Dr. Loren Wold, for cardiac aging expertise; Dr. William Abraham, for clinical cardiology expertise, Dr. William Malarkey, for biology of aging expertise, and Dr. Federica Accornero, for cardiac fibrosis expertise. The hypothesis guided proposal seeks to understand the mechanism by which pathologic gene expression programs are activated in response to aging and inflammation. Diastolic heart failure or heart failure with preserved ejection fraction (HFpEF) is strongly linked with advanced age and inflammation. In HFpEF, the heart's left ventricle does not relax properly (diastolic dysfunction), leading to increased blood volume in the venous and pulmonary systems. HFpEF patients suffer similar morbidity and mortality as patients with systolic dysfunction however, no therapeutics have been found to be effective in the HFpEF population. Given that 3 million Americans are diagnosed with HFpEF and the disease is projected to cost the US over $15 billion annually, there is an urgent need to learn more about this disease and deliver effective therapies to the clinic. This work will test the hypothesis that in response to inflammation and aging, BRD4 coordinately activates pathologic gene programs in cardiomyocytes and cardiac fibroblasts, resulting in fibrosis that drives HFpEF pathogenesis. Preliminary data indicate that pathologic stimulation causes cardiomyocytes to activate neighboring fibroblasts in a BRD4 dependent manner. Cardiomyocytes and fibroblasts will be used to investigate BRD4's role in activation of pro- fibrotic gene expression within the cardiomyocyte to generate pathologic fibroblast activation. Young, middle aged, and advanced aged rats will be used to determine the effect of age on BRD4 function and BRD4 dependent pathologic gene expression. Complementary experiments will be conducted in mice to test BRD4's role in age associated diastolic dysfunction.