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

项目摘要/摘要 以下提案由医学博士Jason Roh，MHS提交，以回应RFA-AG-19-017。卢武铉博士是 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。使用一个 他结合了对老年病学、心脏病学和衰老生物学的兴趣，建立了第一个老年心脏病诊所。 他一直在研究衰老在心力衰竭(HF)中的作用。他目前的资金来源是 美国心脏协会院士奖：研究心衰中激活素II型受体(ActRII)信号 最近被美国心脏病学院和西北大学心血管青年学院认可 调查员奖。在先前研究的基础上，卢武铉博士提出了一项有前景的创新性研究。 翻译潜力，将重点放在ActRII信号在年龄相关的脆弱和心衰。这项建议是基于 他的初步数据表明，分解代谢的ActRII信号会随着年龄的增长而改变，并直接导致心衰 病理生物学。高龄、虚弱和心血管疾病(CVD)之间的强烈关联是很好的- 已经成立了。然而，是否常见的生物机制驱动了这些与年龄相关的病理--以及 重要的是，它们是否能够得到有效的干预--目前尚不清楚。在这里，卢武铉博士提出了一个4- 一年的职业发展计划和指导研究，以实现他的长期职业目标1) 成为心血管疾病衰老生物学领域的领先专家；2)开发治疗老年人心脏病的新疗法 成年人。在MGH心血管研究中心的高效和支持性环境中 和HMS老龄化研究社区，他将与他的导师Anthony Rosenzweig博士和Lewis博士合作 Lipsitz、Jennifer Ho和Dae Kim在这项涵盖衰老、虚弱和HF生物学的综合研究中说。这个 最重要的假设是，ActRII信号的增加在老年人的虚弱和心力衰竭病理生物学中都是原因 靶向抑制ActRII可作为一种治疗策略。这项工作的意义在于 主要有两点：1)心力衰竭是老年人住院的主要原因；2) 目前还没有任何治疗方法可以通过保留射血分数(HFpEF)来提高心力衰竭的死亡率。 老年人心力衰竭的主要原因。值得注意的是，这部作品的翻译潜力在以下方面得到了强调 ActRII抑制剂正在进行临床开发，用于其他适应症(如肌营养不良)，这可能 使他的调查结果能够快速翻译。为了达到他的目标，卢武铉博士将实现以下三个具体目标 目标。AIM 1旨在确定ActRII活性是否与心脏和虚弱表型以及健康相关 老年心力衰竭患者的预后。Aim 2在动物模型中扩展了这些发现，以确定ActRII 信号在年龄相关的虚弱和HFpEF中是原因。最后，目标3，将使用最先进的单细胞RNA 用测序和分子生物学技术阐明ActRII信号调控机制 在老化的心脏和骨骼肌中发挥作用。完成拟议的职业发展计划将 让卢博士成功争取到NIA R01的资金，并成为心血管老龄化领域的领导者。

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.