Activin type II receptor activity in age-related frailty and heart failure

激活素 II 型受体活性在年龄相关的衰弱和心力衰竭中的作用

基本信息

批准号：
10433864
负责人：
JASON DAVID ROH
金额：
$ 24.3万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10433864
关键词：
Activins Activities of Daily Living Acute Aging American American Heart Association Animal Model Aortic Valve Stenosis Automobile Driving Award BMP2 gene Biological Biological Aging Biological Markers Biology Biology of Aging C57BL/6 Mouse Cardiac Cardiology Cardiovascular Diseases Cardiovascular system Cell Aging Cell Cycle Cells Chronic Disease Chronology Clinic Clinical Clinical Research Communities Complex Data Development Development Plans EFRAC Elderly Etiology Expenditure FSTL3 gene Faculty Failure Fibrosis Foundations Frail Elderly Functional disorder Funding Future GDF11 gene GDF8 gene Gap Junctions General Hospitals Genetic Models Geriatrics Goals Health Health Status Heart Heart Diseases Heart failure Hospitalization Human Hypertrophy Impairment Individual Inflammation Lead Learning Ligands Link Longevity Massachusetts Measures Mediator of activation protein Medicare Mentors Metabolism Mission Modeling Molecular Biology Techniques Morbidity - disease rate Mus Muscular Dystrophies Myocardial dysfunction Myocardium National Institute on Aging Outcome Pathologic Pathology Pathway interactions Patients Phenotype Plasma Positioning Attribute Process Proteomics Public Health Quality of life Reagent Receptor Signaling Research Research Personnel Risk Factors Role Signal Transduction Skeletal Muscle Surgical Models System Techniques Therapeutic Translations Treatment Failure Type II Activin Receptors Work activin A age related aged base cardiogenesis career career development cell type clinical development cohort college design frailty heart function human old age (65+)improved inhibitor innovation insight instructor interest loss of function medical schools mortality multicatalytic endopeptidase complex novel novel therapeutic intervention novel therapeutics older patient overexpression pathological aging preservation pressure programs response sarcopenia screening single-cell RNA sequencing supportive environment targeted treatment therapeutic target transcriptome translational potential valve replacement

项目摘要

PROJECT SUMMARY/ABSTRACT The following proposal is submitted by Dr. Jason Roh, MD, MHS, in response to RFA-AG-19-017. Dr. Roh is a cardiologist at Massachusetts General Hospital (MGH) and Instructor at Harvard Medical School (HMS). With a combined interest in geriatrics, cardiology, and aging biology, he established the first geriatric-cardiology clinic at MGH and has been investigating the role of aging in heart failure (HF). He is currently funded by an American Heart Association Fellow-to-Faculty Award to study Activin type II receptor (ActRII) signaling in HF and was recently recognized with American College of Cardiology and Northwestern Cardiovascular Young Investigator’s Awards. Based on his prior research, Dr. Roh is proposing an innovative study with promising translational potential that will focus on ActRII signaling in age-related frailty and HF. This proposal is based on his preliminary data suggesting that catabolic ActRII signaling is altered by aging and directly contributes to HF pathobiology. A strong association between advanced age, frailty, and cardiovascular disease (CVD) is well- established. However, whether common biological mechanisms drive these age-related pathologies – and importantly whether they can be effectively intervened upon – remain unclear. Here, Dr. Roh proposes a 4- year program of career development and mentored research to achieve his long-term career goals of 1) becoming a leading expert in aging biology in CVD and 2) developing novel therapies for heart disease in older adults. Within the highly productive and supportive environment of the MGH Cardiovascular Research Center and the HMS aging research community, he will work with his mentors, Drs. Anthony Rosenzweig, Lewis Lipsitz, Jennifer Ho, and Dae Kim, on this integrated study spanning aging, frailty, and HF biology. The overarching hypothesis is that increased ActRII signaling is causal in both frailty and HF pathobiology in older adults, and that targeted ActRII inhibition can be used as a therapeutic strategy. The significance of this work is highlighted by two major points: 1) HF is the leading cause of hospitalization amongst older adults, and 2) there are currently no therapies that improve mortality in heart failure with preserved ejection fraction (HFpEF), the leading cause of HF in older adults. Notably, the translational potential of this work is underscored by ongoing clinical development of ActRII inhibitors for other indications (e.g. muscular dystrophy), which could enable rapid translation of his findings. To achieve his goals, Dr. Roh will accomplish the following 3 specific aims. Aim 1 is designed to determine if ActRII activity correlates with cardiac and frailty phenotypes and health outcomes in older HF patients. Aim 2 expands on these findings in animal models to determine if ActRII signaling is causal in age-related frailty and HFpEF. Lastly Aim 3, will use state-of-the-art single cell RNA sequencing and molecular biology techniques to elucidate mechanisms by which ActRII signaling modulates function in the aging heart and skeletal muscle. Completion of the proposed career development plan will position Dr. Roh to successfully compete for NIA R01 funding and become a leader in cardiovascular aging.

项目概要/摘要以下提案由 Jason Roh 博士（医学博士、MHS）针对 RFA-AG-19-017 提交。马萨诸塞州总医院 (MGH) 的心脏病专家和哈佛医学院 (HMS) 的讲师。结合对老年病学、心脏病学和衰老生物学的兴趣，他建立了第一个老年心脏病学诊所他在麻省总医院 (MGH) 一直在研究衰老在心力衰竭 (HF) 中的作用，目前由一家机构资助。美国心脏协会院士奖研究心力衰竭中的激活素 II 型受体 (ActRII) 信号传导最近获得美国心脏病学会和西北心血管青年学会的认可研究者奖基于他之前的研究，Roh 博士提出了一项具有前景的创新研究。该提案基于 ActRII 信号传导在年龄相关的衰弱和心力衰竭中的转化潜力。他的初步数据表明，分解代谢 ActRII 信号传导会因衰老而改变，并直接导致心力衰竭高龄、虚弱和心血管疾病 (CVD) 之间存在密切关联。然而，是否有共同的生物机制驱动这些与年龄相关的病症——以及重要的是，是否可以对其进行有效干预——仍不清楚，卢博士在此提出了 4-。年职业发展计划和指导研究，以实现他的长期职业目标 1) 成为 CVD 衰老生物学领域的领先专家，2) 开发针对老年人心脏病的新疗法在麻省总医院心血管研究中心的高生产力和支持性环境中。和 HMS 老龄化研究界，他将与他的导师 Anthony Rosenzweig、Lewis 博士一起工作。 Lipsitz、Jennifer Ho 和 Dae Kim 进行了这项涵盖衰老、虚弱和心力衰竭生物学的综合研究。总体假设是，ActRII 信号传导增加与老年人的虚弱和心力衰竭病理学有关。成人，并且靶向ActRII抑制可以作为一种治疗策略，这项工作的意义在于。强调了两个要点：1) 心力衰竭是老年人住院的主要原因，2) 目前没有任何疗法可以改善射血分数保留的心力衰竭（HFpEF）的死亡率，值得注意的是，这项工作的转化潜力被强调了。针对其他适应症（例如肌营养不良症）的 ActRII 抑制剂正在进行的临床开发，这可能为了实现他的目标，Roh 博士将实现以下 3 个具体目标。目标 1 旨在确定 ActRII 活性是否与心脏和虚弱表型以及健康相关。目标 2 扩展了动物模型中的这些发现，以确定 ActRII 是否有效。最后的目标 3 将使用最先进的单细胞 RNA。测序和分子生物学技术阐明 ActRII 信号调节机制完成所提出的职业发展计划将改善心脏和骨骼肌的功能。使 Roh 博士能够成功竞争 NIA R01 资金并成为心血管衰老领域的领导者。