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

• 批准号: 9811610
• 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
• 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/9811610
• 关键词: Activins; Activities of Daily Living; Acute; Aging; American; American Heart Association; Animal Model; Aortic Valve Stenosis; Automobile Driving; Award; 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; Structure; Surgical Models; System; Techniques; Therapeutic; Translations; Treatment Failure; Type II Activin Receptors; Work; activin A; age related; aged; base; bone morphogenetic protein 2; cardiogenesis; career; career development; cell type; clinical development; cohort; college; design; frailty; heart function; human old age (65+); improved; inhibitor/antagonist; 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; valve replacement

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.

项目摘要/摘要 以下提案由MHS医学博士Jason Roh博士提交，以回应RFA-AG-19-017。 Roh博士是一个 马萨诸塞州综合医院（MGH）的心脏病专家和哈佛医学院（HMS）的讲师。与 他对老年医学，心脏病学和衰老生物学的兴趣结合了兴趣，他建立了第一个老年病学诊所 在MGH，一直在研究衰老在心力衰竭（HF）中的作用。他目前由 美国心脏协会的研究授予研究激活素II型接收器（ACTRII）信号的同伴奖。 并最近获得美国心脏病学院和西北心血管幼儿学院的认可 调查员的奖项。基于他的先前研究，Roh博士提出了一项具有Promise的创新研究 转化潜力将集中在与年龄相关的脆弱和HF中的ACTRII信号传导。该提议基于 他的初步数据表明，分解代谢的ACTRII信号通过衰老改变，直接有助于HF 病理生物学。高龄，脆弱和心血管疾病（CVD）之间的密切关联是很好的 已确立的。但是，常见的生物学机制是否驱动了这些与年龄有关的病理 - 以及 重要的是，它们是否可以有效地干预 - 尚不清楚。在这里，Roh博士提案4- 职业发展的年度计划和修改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 成年人。在MGH心血管研究中心高产和支持性的环境中 和HMS老化的研究社区，他将与他的导师博士一起工作。安东尼·罗森兹威（Anthony Rosenzweig），刘易斯（Lewis） Lipsitz，Jennifer Ho和Dae Kim在这项综合研究中，涵盖了衰老，脆弱和HF生物学。这 总体假设是，在较老的脆弱和HF病理学中，ACTRII信号的增加是因果关系 成人，而靶向的ACTRII抑制可以用作治疗策略。这项工作的意义是 有两个主要点突出显示：1）HF是老年人住院的主要原因，2） 目前没有疗法可以通过保留的射血分数（HFPEF）改善心力衰竭死亡率， 老年人HF的主要原因。值得注意的是，这项工作的翻译潜力被强调 其他适应症的ACTRII抑制剂的临床开发（例如，肌肉营养不良）可能 可以快速翻译他的发现。为了实现他的目标，Roh博士将完成以下3个特定的特定 目标。 AIM 1旨在确定ACTRII活性是否与心脏和脆弱的表型和健康相关 老年HF患者的结果。 AIM 2在动物模型中扩展了这些发现，以确定ACTRII是否是ACTRII 信号传导是与年龄相关的脆弱和HFPEF的因果关系。最后AIM 3，将使用最新的单细胞RNA 测序和分子生物学技术以阐明Actrii信号传导调节的机制 在衰老的心脏和骨骼肌中起作用。拟议的职业发展计划的完成将 将ROH博士定位为成功竞争NIA R01资金，并成为心血管衰老的领导者。