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.

项目概要/摘要 以下提案由夏鹏博士针对 PA-20-190 提交。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。 首次提交 K01 后，他已晋升为哈佛医学院 (HMS) 的医学讲师。 夏博士提出了一个全面的五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的独立研究者，2) 为了实现这些目标，夏博士开发了针对患有心血管疾病的老年人的治疗小说。 主要由 MGH CVRC 主任 Paul Yu 博士（医学博士、哲学博士）和国际公认的 血管和激活素生物学专家 Jason Roh 博士（医学博士、MHS）（NIA Beeson）也将共同指导。 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）将接受培训。 由科学咨询委员会补充，包括 Jennifer Ho 博士、Ariela Orkaby 医学博士、公共卫生硕士、 安东尼·罗森茨威格 (Anthony Rosenzweig) 医学博士将在心脏衰老、心力衰竭和 夏博士将在 MGH CVRC 的世界级科学环境中进行研究。 HMS，并将积极参与培训中概述的丰富的当地和国家老龄化研究社区 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。 为他开辟新的研究领域，并促进他发展成为心血管衰老科学的未来领导者。 夏博士生成了大部分初步数据，为这一创新提案奠定了基础。 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。 与射血分数保留（HFpEF）相关的心力衰竭他的总体假设是病理性的。 衰老会上调内皮 ActRII 信号传导，从而诱导标志性的心脏微血管稀疏， 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。 1) HFpEF 也强调了这项工作的重要性。 是老年人发病和死亡的主要原因，2) 治疗选择有限 在这项提案中，夏博士将严格研究内皮细胞的功能作用。 ActRII 信号在与年龄相关的 HFpEF 中的 3 个目标旨在确定是否与年龄相关的内皮细胞。 ActRII 激活导致 HFpEF 的心脏功能障碍；Aim 2 将利用先进的成像方法来 确定内皮 ActRII 激活是否会引起微血管稀疏和炎症；目标 3 阐明年龄相关 HFpEF 中内皮细胞 ActRII 信号传导的分子机制 完成拟议的职业和研究计划将使夏博士取得成功。 竞争NIA R01资助并成为心血管衰老生物学研究的独立研究者。