Activin-Mediated Autophagy During Cardiac Aging

描述(申请人提供)：年龄是多种人类疾病的主要风险因素，如癌症、糖尿病、神经退行性变和心脏病。具体地说，老龄化与心源性猝死(SCD)的高发病率有关，SCD是西方国家的主要死亡原因。与老龄化相关的心脏病的治疗和费用造成了巨大的个人、社会和经济负担。解决心脏病的致病机制是基础和转化性衰老研究的紧迫目标。在包括心肌在内的所有细胞中，泛素-蛋白酶体系统(UPS)和自噬/溶酶体系统提供蛋白降解机制来调节蛋白质的周转和降解。通过自噬有效地清除蛋白质聚集体和受损的线粒体可能是维持心脏内环境平衡和心脏功能的关键。虽然自噬减少与许多年龄相关的心脏疾病有关，但尚不清楚随年龄变化的自噬是一个促成因素，还是仅仅是对心脏衰老的反应。我们最近发现，转化生长因子-β超家族成员激活素信号是果蝇长寿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发展的情况目前知之甚少。为了进一步了解苍蝇肌肉的潜在机制，并将我们在苍蝇肌肉中的发现转化为哺乳动物的研究，我们将研究激活素在苍蝇心脏老化中的作用，并同时在兔心脏衰老模型的同种心肌细胞中发挥作用。具体地说，我们将利用果蝇细胞培养来确定激活素信号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功能(目标2)。最后，我们将把我们在Fly上的发现转化为哺乳动物的心脏系统，通过解剖激活素信号在老化的兔心肌细胞中对自噬和组织动态平衡的调节(目标3)。更好地理解维持心脏组织内稳态的分子机制对于制定预防衰老期间心脏功能障碍的治疗策略至关重要。这一《独立之路》奖项将在多个方面帮助花白博士实现他的职业目标，并帮助他向独立调查员过渡。白博士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关于功能老化和与年龄相关的疾病的基础研究，重点是自噬及其在心脏老化中的作用。在K99培训阶段，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)心脏老化的实验系统来建立自己的翻译专业知识。虽然他将继续接受马克·鞑靼博士的指导，但白博士将接受罗德岛医院心血管研究中心(CVRC)主任吉迪恩·科伦博士和桑福德·伯纳姆医学研究所发展和老龄化项目主任罗尔夫·博德默博士的培训。科伦博士和博德默博士都是心脏老化和疾病领域的专家。白博士将利用这一独特的培训机会，培养他将心脏功能研究从果蝇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.