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

内皮 ActRII 信号传导在射血分数保留的年龄相关性心力衰竭 (HFpEF) 中的作用

• 批准号: 10739935
• 负责人: Peng Xia
• 金额: $ 12.93万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-15 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10739935
• 关键词: Acceleration; Activins; Activities of Daily Living; Advisory Committees; Age; Aging; Area; Attenuated; Automobile Driving; Biology; Biology of Aging; Blood Vessels; Cardiac; Cardiovascular Diseases; Cardiovascular system; Cell Aging; Cells; Chronic; Clinical; Communities; Complex; Coronary; Data; Development; Doctor of Philosophy; EFRAC; Elderly; Endothelial Cells; Endothelium; Environment; FDA approved; Fostering; Foundations; Functional disorder; Funding; Future; General Hospitals; Genetic Transcription; Goals; Heart; Heart failure; Human; ICAM1 gene; Image; Immune; Incidence; Inflammation; Inflammatory; International; Investigation; Lead; Leukocytes; Longevity; Massachusetts; Mediating; Mediator; Medicine; Mentors; Methods; Mission; Modeling; Molecular; Morbidity - disease rate; Mus; Myocardial dysfunction; Myocarditis; NF-kappa B; National Institute on Aging; Pathologic; Pathway interactions; Patients; Pharmacological Treatment; Phenotype; Phosphorylation; Physiological; Play; Positioning Attribute; Process; Property; Public Health; Receptor Activation; Receptor Inhibition; Receptor Signaling; Regulation; Research; Research Personnel; Role; Science; Signal Induction; Signal Transduction; Stress; Syndrome; Therapeutic; Training; Transgenic Organisms; Type II Activin Receptors; United States National Institutes of Health; Vascular Endothelial Cell; Work; activin A; age related; aged; cardiometabolism; career; career development; design; frailty; functional restoration; imaging modality; improved; in vivo Model; inhibitor; innovation; instructor; knowledge base; medical schools; middle age; mortality; nanoparticle; novel; novel strategies; novel therapeutics; p65; paracrine; pathological aging; preservation; programs; recruit; response; senescence; skills; therapeutic target; translational potential; vascular inflammation

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.

项目摘要/摘要 PA-Xia博士对PA-20-190的回应提交了以下提案。夏目前是NIH 马萨诸塞州综合医院心血管研究中心（MGH CVRC）的T32研究员。自从他 最初的K01提交，他已晋升为哈佛医学院（HMS）医学教练。这里， Xia博士提出了一项全面的5年职业发展计划，并修改了研究以实现 他的长期职业目标是1）成为心血管衰老生物学领域的独立研究者，以及2） 为患有心血管疾病的老年人开发新的疗法。为了实现这些目标，夏 MGH CVRC主任Paul Yu博士主要由医学博士Paul Yu博士和国际公认的指导 血管和激活生物学专家。 Xia博士还将由MHS的Jason Roh博士（Nia Beeson）授予 学者，心脏老化专家）和医学博士Aaron Aguirre博士（高级成像专家）。他的训练将是 由包括Drs在内的科学咨询委员会的补充。医学博士Jennifer Ho，Ariela Orkaby，医学博士，MPH， 以及医学博士Anthony Rosenzweig，他们将在心脏衰老，心力衰竭和 脆弱的生物学。 Xia博士将在MGH CVRC的世界一流科学环境中进行研究 HMS，并将积极参与培训中概述的富裕地方和国家老化的研究社区 计划。该计划是专门设计的，旨在提高Xia博士的知识库和科学技能 为他提供新的投资领域，并促进他作为心血管衰老科学领域未来领导者的发展。 Xia博士生成了大多数初步数据，为这项创新提案奠定了基础。这里， 他试图研究内皮激活素II型受体（ACTRII）信号在年龄 - 年龄 - 与保留的射血分数（HFPEF）相关的心力衰竭。他的总体假设是病理 衰老的上调内皮ACTRII信号传导，该信号传导诱导了标志性心脏微血管罕见和 在HFPEF中观察到的炎症表型。这项工作具有ACTRII抑制剂的高转化潜力 被FDA批准用于其他临床适应症。这项工作的重要性也由1）HFPEF突出显示 是老年人发病和死亡率的主要原因，以及2）有限的治疗选择 流行的老年HF综合征。在此提案中，Xia博士将严格研究内皮的功能作用 与年龄相关的HFPEF的ACTRII信号在3个目标中。 AIM 1旨在确定是否与年龄相关的内皮 ACTRII激活导致HFPEF的心脏功能障碍； AIM 2将利用高级成像方法 确定内皮ACTRII激活是否诱导微血管稀疏和注射； AIM 3将 阐明与年龄相关的HFPEF中的内皮细胞ACTRII信号的分子机制 病理生理学。拟议的职业和研究计划的完成将使Xia博士成功地定位 争夺NIA R01资金，并成为心血管衰老生物学研究的独立研究者。