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

项目概要/摘要 以下提案由MHS医学博士Jason Roh提交，以响应RFA-AG-19 - 017。卢武铉是一位 马萨诸塞州总医院（MGH）心脏病专家和哈佛医学院（HMS）讲师。与 结合对老年医学、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 他一直在研究衰老在心力衰竭（HF）中的作用。他目前由一名 美国心脏协会研究员对教师奖，研究HF中的激活素II型受体（ActRII）信号传导 最近被美国心脏病学会和西北心血管年轻人协会认可， 调查员奖。基于他先前的研究，卢博士提出了一项创新的研究， 翻译潜力，将集中在年龄相关的虚弱和HF中的ActRII信号传导。该提案基于 他的初步数据表明，分解代谢ActRII信号被老化改变，并直接导致HF， 病理生物学高龄、虚弱和心血管疾病（CVD）之间的强相关性是很好的- 确立了习然而，是否共同的生物学机制驱动这些与年龄有关的病理-以及 更重要的是，是否能够有效地干预这些行动，目前还不清楚。在这里，卢博士提出了一个4- 一年的职业发展和指导研究计划，以实现他的长期职业目标1） 成为CVD衰老生物学的领先专家，2）开发老年人心脏病的新疗法 成年人了在MGH心血管研究中心的高效和支持性环境中 和HMS老化研究社区，他将与他的导师，博士安东尼罗森茨威格，刘易斯 Lipsitz，Jennifer Ho和Dae Kim，关于这项涵盖衰老，虚弱和HF生物学的综合研究。的 总体假设是，增加的ActRII信号传导在老年人的虚弱和HF病理生物学中是因果关系， 成人，并且靶向ActRII抑制可用作治疗策略。这项工作的意义在于 主要有两点：1）HF是老年人住院的主要原因，以及2） 目前没有改善射血分数保留的心力衰竭（HFpEF）的死亡率的疗法， 老年人心力衰竭的主要原因。值得注意的是，这项工作的翻译潜力是强调， 正在进行的ActRII抑制剂用于其他适应症（例如肌营养不良症）的临床开发， 使他的发现能迅速转化。为了实现他的目标，卢博士将完成以下3项具体工作 目标。目的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HF患者的结局。目的2在动物模型中扩展了这些发现，以确定ActRII是否 信号传导在年龄相关的虚弱和HFpEF中是因果关系。最后，目标3，将使用最先进的单细胞RNA 测序和分子生物学技术来阐明ActRII信号调节的机制 在衰老的心脏和骨骼肌中发挥作用。完成拟议的职业发展计划将 使卢博士能够成功地竞争NIA R01基金，并成为心血管衰老领域的领导者。

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.