PROJECT SUMMARY/ABSTRACT The following proposal is submitted by Dr. Peng Xia, PhD, in response to PA-20-190. Dr. Xia is currently a NIH T32 fellow in the Massachusetts General Hospital Cardiovascular Research Center (MGH CVRC). Since his initial K01 submission, he has been promoted to Instructor in Medicine at Harvard Medical School (HMS). Here, Dr. Xia proposes a comprehensive 5-year program of career development and mentored research to achieve his long-term career goals of 1) becoming an independent investigator in cardiovascular aging biology and 2) developing novel therapeutics for older adults with cardiovascular disease. To accomplish these goals, Dr. Xia will be primarily mentored by Dr. Paul Yu, MD, PhD, Director of the MGH CVRC and an internationally-recognized expert in vascular and Activin biology. Dr. Xia will also be co-mentored by Dr. Jason Roh, MD, MHS (NIA Beeson scholar, Cardiac aging expert) and Dr. Aaron Aguirre, MD, PhD (advanced imaging expert). His training will be supplemented by a Scientific Advisory Committee, including Drs. Jennifer Ho, MD, Ariela Orkaby, MD, MPH, and Anthony Rosenzweig, MD, who will provide complementary expertise in cardiac aging, heart failure, and frailty biology. Dr. Xia will conduct his research in the world class scientific environments of the MGH CVRC and HMS, and will actively engage in the rich local and national aging research communities outlined in his training plan. The plan has been specifically designed to advance Dr. Xia’s knowledge base and scientific skills in this new area of investigation for him, and foster his development as a future leader in cardiovascular aging science. Dr. Xia has generated most of the preliminary data that provides the foundation for this innovative proposal. Here, he seeks to investigate a potential causal role of endothelial Activin type II receptor (ActRII) signaling in age- related heart failure with preserved ejection fraction (HFpEF). His overarching hypothesis is that pathological aging upregulates endothelial ActRII signaling, which induces the hallmark cardiac microvascular rarefaction and inflammatory phenotypes observed in HFpEF. This work has high translational potential with ActRII inhibitors being FDA-approved for other clinical indications. The significance of this work is also highlighted by 1) HFpEF being a leading cause of morbidity and mortality in older adults, and 2) the limited therapeutic options for this prevalent geriatric HF syndrome. In this proposal, Dr. Xia will rigorously study the functional role of endothelial ActRII signaling in age-related HFpEF in 3 aims. Aim 1 is designed to determine if age-associated endothelial ActRII activation contributes to cardiac dysfunction in HFpEF; Aim 2 will utilize advanced imaging methods to determine if endothelial ActRII activation induces microvascular rarefaction and inflammation; and Aim 3 will elucidate the molecular mechanism(s) underlying endothelial cell ActRII signaling in age-relate...