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 以下提案由彭霞博士针对PA-20-190提交。夏博士目前是美国国立卫生研究院的 麻省总医院心血管研究中心(MGH CVRC)T32研究员。因为他的 在最初提交的K01文件中，他已被提升为哈佛医学院(HMS)的医学讲师。这里, 夏博士提出了一项全面的5年职业发展计划和指导研究，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员；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MGH CVRC主任、医学博士、博士Paul Yu指导，他是国际公认的 血管和激活素生物学专家。夏博士还将由医学博士Jason Roh，MHS(NIA Beeson)共同指导 Aaron Aguirre博士，医学博士，博士(高级影像专家)。他的训练将是 由科学顾问委员会补充，成员包括何珍妮博士，医学博士，Ariela Orkaby，医学博士，公共卫生硕士， 和Anthony Rosenzweig医学博士，他们将在心脏老化、心力衰竭和 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，并 HMS，并将积极参与他在培训中概述的丰富的地方和国家老龄研究社区 计划。该计划是专门为提高夏博士在这方面的知识基础和科学技能而设计的 为他开辟了新的研究领域，并促进了他作为心血管衰老科学未来领导者的发展。 夏博士提供了大部分初步数据，这些数据为这项创新的提案奠定了基础。这里, 他试图研究内皮激活素II型受体(ActRII)信号在年龄- 保留射血分数(HFpEF)的相关性心力衰竭。他的首要假设是病态的 衰老上调内皮细胞ActRII信号，从而导致心脏微血管稀疏和 HFpEF中观察到的炎症表型。这项工作对ActRII抑制剂具有很高的翻译潜力 正被FDA批准用于其他临床适应症。这项工作的重要性也通过1)HFpEF突显出来 是老年人发病率和死亡率的主要原因，以及2)治疗选择有限 流行的老年性心衰综合征。在这项提案中，夏博士将严格研究内皮细胞的功能作用 3个AIMS的年龄相关性HFpEF中的ActRII信号。AIM 1旨在确定年龄相关的内皮细胞 ActRII激活有助于HFpEF中的心功能障碍；AIM 2将利用先进的成像方法 确定内皮细胞ActRII激活是否会导致微血管疏松和炎症；Aim 3将 老年高血压性心衰内皮细胞ACTRII信号转导的分子机制(S) 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 争夺NIA R01资金，成为心血管衰老生物学研究的独立研究员。