The role of endothelial ActRII signaling in age-related Heart Failure with preserved Ejection Fraction (HFpEF)

项目总结/摘要 以下提案由Peng Xia博士提交，以回应PA-20-190。夏博士目前是NIH 马萨诸塞州总医院心血管研究中心（MGH CVRC）的T32研究员。自从他 最初的K 01提交，他已晋升为医学讲师在哈佛医学院（HMS）。在这里， 博士夏提出了一项全面的5年职业发展和指导研究计划，以实现 他的长期职业目标是：1）成为心血管衰老生物学的独立研究者; 2） 为患有心血管疾病的老年人开发新的治疗方法。为了实现这些目标，夏博士 将主要由Paul Yu博士，MD，PhD，MGH CVRC主任和国际公认的 血管和激活素生物学专家。Xia博士还将由MHS（NIA Beeson）医学博士Jason Roh共同指导 学者、心脏衰老专家）和Aaron Aguirre博士，医学博士、博士（高级成像专家）。他的训练将是 由科学咨询委员会补充，包括Jennifer Ho博士，医学博士，Ariela Orkaby，医学博士，公共卫生硕士， 和安东尼罗森茨韦格，医学博士，谁将提供补充专业知识，在心脏老化，心力衰竭， 脆弱的生物学夏博士将在MGH CVRC的世界级科学环境中进行研究， HMS，并将积极参与丰富的地方和国家老龄化研究社区概述了他的培训 计划该计划是专门设计来提高夏博士的知识基础和科学技能， 新的研究领域，并促进他作为心血管衰老科学未来领导者的发展。 博士Xia提供了大部分初步数据，为这一创新提案提供了基础。在这里， 他试图研究内皮激活素II型受体（ActRII）信号在年龄增长中的潜在因果作用， 射血分数保留相关心力衰竭（HFpEF）。他的首要假设是， 衰老上调内皮细胞ActRII信号传导，这诱导了标志性的心脏微血管稀疏， 在HFpEF中观察到的炎性表型。这项工作具有很高的翻译潜力与ActRII抑制剂 FDA批准用于其他临床适应症。这项工作的重要性也突出了1）HFpEF 是老年人发病率和死亡率的主要原因，以及2）对此的治疗选择有限 流行的老年HF综合征。在这项提案中，夏博士将严格研究内皮细胞的功能作用， 在3个目标中年龄相关HFpEF中的ActRII信号传导。目的1旨在确定是否与年龄相关的内皮细胞 ActRII激活导致HFpEF患者心功能不全; Aim 2将利用先进的成像方法， 确定内皮ActRII激活是否诱导微血管稀疏和炎症;目标3将 阐明年龄相关HFpEF中内皮细胞ActRII信号转导的分子机制 病理生理学完成拟议的职业生涯和研究计划将使夏博士成功地 竞争NIA R 01资金，并成为心血管衰老生物学研究的独立研究者。

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-related HFpEF pathophysiology. Completion of the proposed career and research plans will position Dr. Xia to successfully compete for NIA R01 funding and become an independent investigator in cardiovascular aging biology research.