Activin-Mediated Autophagy During Cardiac Aging

描述（由申请人提供）：年龄是许多人类疾病的主要危险因素，如癌症、糖尿病、神经退行性疾病和心脏病。具体而言，衰老与心脏性猝死（SCD）的高发有关，而心脏性猝死是西方国家的主要死亡原因。与衰老有关的心脏病的治疗和费用给个人、社会和经济造成了沉重负担。解决心脏疾病的致病机制是基础和转化衰老研究的迫切目标。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质水解机制来调节蛋白质的周转和降解。通过自噬有效清除蛋白质聚集体和受损线粒体可能对维持心脏稳态和心功能至关重要。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一个促成因素还是仅仅是对心脏衰老的反应，目前尚不清楚。我们最近发现激活素信号是TGF-β超家族的一员，是果蝇寿命和肌肉自噬的调节因子。激活素信号是否以及如何影响心肌病或其随年龄的发展，目前知之甚少。为了进一步了解潜在的机制，并将我们在苍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的苍蝇心脏中的作用，同时在兔子心脏衰老模型的同源心肌细胞中也有作用。具体来说，我们将通过激活素信号控制果蝇细胞培养的自噬的分子机制（目的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（目的2）。最后，我们将通过解剖衰老兔心肌细胞中激活素信号对自噬和组织稳态的调节，将我们在苍蝇中的发现转化为哺乳动物心脏系统（目的3）。更好地了解心脏组织稳态维持的分子机制将对预防衰老过程中心功能障碍的治疗策略的发展至关重要。这个“独立之路”奖将在许多方面帮助白华博士实现他的职业目标，并帮助他过渡到一个独立的研究者。他的长期职业目标是在一所主要的研究型大学或生物医学研究所建立一个独立的项目，在那里他将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训练阶段，白博士将通过同时学习果蝇和兔子心脏（一种特殊的人类模型）的心脏老化实验系统来建立自己的翻译专业知识。他将继续接受Marc Tatar医生的指导，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Sanford Burnham医学研究所发展与衰老项目主任Rolf Bodmer博士的培训。Koren博士和Bodmer博士都是心脏老化和疾病领域的专家。白博士将利用这次独特的培训机会，发展他将果蝇心脏功能研究转化为哺乳动物的能力。

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-β 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.