Activin-Mediated Autophagy During Cardiac Aging

心脏衰老过程中激活素介导的自噬

• 批准号: 8917842
• 负责人: Hua Bai
• 金额: $ 9.45万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8917842
• 关键词: Action Potentials; Activins; Age; Aging; Animal Model; Autophagocytosis; Autophagosome; Award; Basic Science; Biological Assay; Biomedical Research; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cardiovascular system; Cause of Death; Cell Culture Techniques; Cells; Complex; Country; Cytoplasm; Development; Diabetes Mellitus; Disease; Drosophila genus; Economic Burden; Educational process of instructing; Elderly; Excision; Exhibits; Gene Expression; Genes; Genetic; Genetic screening method; Goals; Health; Heart; Heart Diseases; Heart failure; Homeostasis; Hospitals; Human; Incidence; Invertebrates; Lead; Learning; Ligands; Link; Longevity; Lysosomes; Maintenance; Malignant Neoplasms; Mammals; Measures; Mediating; Medical Research; Mentors; Mitochondria; Modeling; Molecular; Monitor; Muscle; Mutation; Myocardial; Myocardial dysfunction; Myocardium; Nerve Degeneration; Organelles; Oryctolagus cuniculus; Pathology; Pathway interactions; Phase; Premature aging syndrome; Process; Proteins; RNA Interference; Regulation; Research; Research Institute; Research Personnel; Rhode Island; Risk Factors; Role; Signal Pathway; Signal Transduction; Skeletal Muscle; System; Therapeutic Intervention; Tissues; Training; Translating; Treatment Cost; Ubiquitin; Universities; Work; age effect; age related; anti aging; career; fly; genetic manipulation; heart function; human disease; inhibitor/antagonist; member; multicatalytic endopeptidase complex; novel; prevent; programs; protein aggregate; protein aggregation; protein degradation; receptor; response; senescence; small molecule; sudden cardiac death; therapeutic development; tool

DESCRIPTION (provided by applicant): Age is a major risk factor for a wide range of human diseases, such as cancer, diabetes, neurodegeneration and heart disease. Specifically, aging is associated with high incidence of sudden cardiac death (SCD), the leading cause of death in western countries. The treatment and costs associated with aging-related heart disease contribute to substantial personal, societal and economic burdens. Resolving the contributing mechanisms of heart disease is a pressing goal of basic and translational aging research. In all cells, including those of heart muscle, the ubiquitin-proteasome system (UPS) and autophagy/lysosome system provide proteolytic mechanisms to regulate protein turnover and degradation. The effective removal of protein aggregates and damaged mitochondria via autophagy might be crucial for the maintenance of homeostasis in heart and cardiac function. Although reduced autophagy is associated with many age-related heart diseases, it remains unknown whether altered autophagy with age is a contributing factor or merely a response to cardiac senescence. We have recently identified Activin signaling, a member of the TGF-ß superfamily, as a regulator for longevity and muscle autophagy in Drosophila. Very little is known whether and how Activin signaling might influence cardiomyopathy or its progression with age. In order to further understand the underlying mechanisms and translate our discovery in fly muscle to mammalian research, we will investigate the role of Activin in aging fly heart and simultaneously in homologous cardiomyocytes of a rabbit model of heart aging. Specifically, we will identify the molecular mechanisms through which Activin signaling controls autophagy using Drosophila cell culture (Aim 1). We will then determine how Activin signaling modulates myocardial cell autophagy and heart function of aging Drosophila (Aim 2). Finally we will translate our discovery in fly to mammalian cardiac system by dissecting the regulation of autophagy and tissue homeostasis by Activin signaling in aging rabbit cardiomyocytes (Aim 3). A better understanding of molecular mechanisms underlying the maintenance of heart tissue homeostasis will be critical for the development of therapeutic strategies for preventing cardiac dysfunction during aging. This "Pathway to Independence" award will help Dr. Hua Bai to achieve his career goal in many ways and help his transition to an independent investigator. Dr. Bai's long-term career goal is to establish an independent program at a major research university or biomedical research institute where he will lead and teach basic research on functional aging and age-related diseases, with an emphasis on autophagy and its roles in cardiac aging. During the K99 training phase, Dr. Bai will build his own translational expertise by simultaneously learning experimental systems of cardiac aging with Drosophila and the rabbit heart (an exceptional human model). While he will continue to be mentored by Dr. Marc Tatar, Dr. Bai will train with Dr. Gideon Koren, Director of Cardiovascular Research Center (CVRC) of Rhode Island Hospital, and Dr. Rolf Bodmer, Director of Development and Aging Program at Sanford Burnham Medical Research Institute. Both Dr. Koren and Dr. Bodmer are the experts in the field of cardiac aging and diseases. Dr. Bai will take advantage of this unique training opportunity to develop his capacity to translate research on cardiac function from Drosophila to mammals.

描述（由申请人提供）：年龄是多种人类疾病的主要危险因素，例如癌症、糖尿病、神经退行性疾病和心脏病。具体而言，衰老与心源性猝死（SCD）的高发生率有关，而心源性猝死是西方国家的主要原因。与衰老相关的心脏病相关的治疗和费用造成巨大的个人、社会和经济负担。解决心脏病的发病机制是基础和转化衰老研究的一个紧迫目标。在所有细胞中，包括心肌细胞，泛素蛋白酶体系统 (UPS) 和自噬/溶酶体系统提供蛋白水解机制来调节蛋白质周转和降解。通过自噬有效去除蛋白质聚集体和受损线粒体可能对于维持心脏和心脏功能的稳态至关重要。尽管自噬减少与许多与年龄相关的心脏病有关，但随着年龄的增长而改变的自噬是否是一个促成因素或仅仅是对心脏衰老的反应仍不清楚。我们最近发现激活素信号传导（TGF-β 超家族的成员）可以作为果蝇寿命和肌肉自噬的调节因子。目前对于激活素信号传导是否以及如何影响心肌病或其随年龄的进展的情况知之甚少。为了进一步了解潜在机制并将我们在果蝇肌肉中的发现转化为哺乳动物研究，我们将研究激活素在衰老果蝇心脏中的作用，同时在兔心脏衰老模型的同源心肌细胞中的作用。具体来说，我们将利用果蝇细胞培养物确定激活素信号传导控制自噬的分子机制（目标 1）。然后我们将确定激活素信号如何调节衰老果蝇的心肌细胞自噬和心脏功能（目标 2）。最后，我们将通过剖析衰老兔心肌细胞中激活素信号传导对自噬和组织稳态的调节，将我们在果蝇中的发现转化为哺乳动物心脏系统（目标 3）。更好地了解维持心脏组织稳态的分子机制对于制定预防衰老过程中心脏功能障碍的治疗策略至关重要。此次“独立之路”奖项将帮助白华博士在多方面实现其职业目标，并帮助他向独立研究者转型。白博士的长期职业目标是在主要研究型大学或生物医学研究所建立独立项目，领导和教授功能性衰老和年龄相关疾病的基础研究，重点是自噬及其在心脏衰老中的作用。在K99培训阶段，白博士将通过以下方式建立自己的翻译专业知识： 同时学习果蝇和兔子心脏（一种特殊的人类模型）心脏老化的实验系统。白博士将继续接受 Marc Tatar 博士的指导，同时还将接受罗德岛医院心血管研究中心 (CVRC) 主任 Gideon Koren 博士和桑福德伯纳姆医学研究所发育与衰老项目主任 Rolf Bodmer 博士的培训。 Koren博士和Bodmer博士都是心脏衰老和疾病领域的专家。白博士将利用这一独特的培训机会来发展他将果蝇心脏功能研究成果转化为哺乳动物的能力。