Restore energy capacity in the aging heart

恢复衰老心脏的能量容量

• 批准号: 9297564
• 负责人: QINGLIN YANG
• 金额: $ 7.43万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9297564
• 关键词: ATP Hydrolysis; ATP Synthesis Pathway; Adenoviruses; Aging; Aging-Related Process; Attenuated; Biochemical; Cardiac; Cardiac development; Cardiomyopathies; Chickens; Congestive Heart Failure; Defect; Dependovirus; Development; Down Syndrome; Energy Metabolism; Enhancers; Escherichia coli; Gene Targeting; Genes; Heart; Heart Hypertrophy; Heart failure; Hypertrophy; Impairment; Lead; Left; Link; Mechanical Stress; Mediating; Metabolic; Mitochondria; Mitochondrial Proteins; Mitochondrial Proton-Translocating ATPases; Molecular; Morphology; Multienzyme Complexes; Mus; Myocardial; Myocardial Infarction; Myocardial dysfunction; Myocardium; Names; Outcome; Oxidation-Reduction; PPAR alpha; Pathologic; Patients; Phenotype; Physiologic intraventricular pressure; Pilot Projects; Play; Primary idiopathic dilated cardiomyopathy; Production; Proteins; Regulation; Respiration; Role; Serotyping; Signal Transduction; Skeletal Muscle; Stimulus; Structure; Testing; Therapeutic; Tissues; Transgenic Organisms; Troponin T; Viral Vector; aging population; base; effective intervention; gene therapy; human disease; improved; inhibitor/antagonist; innovation; mitochondrial dysfunction; mitochondrial metabolism; new therapeutic target; novel; overexpression; pre-clinical; pressure; promoter; protein expression; response; restoration; therapeutic gene

Mitochondria play a central role in energy metabolism and redox regulation. Over the last decade, accumulating evidence has suggested a causative link between mitochondrial dysfunction and major phenotypes associated with aging of various tissues, including the heart. The aging heart is subjected to cardiac hypertrophy, especially when under mechanical stress, such as left ventricular pressure overload. ATP synthase is a key enzyme complex generating ATP in mitochondria, thus playing a central role in mitochondrial function. Functional defects of ATP synthase can cause and aggravate human diseases, such as cardiomyopathy and congestive heart failure, especially in aging population. However, it remains unclear if impaired mitochondrial ATP synthase is one of the underlying mechanism of energy deficiency and mitochondrial dysfunction in the aging heart. We have recently identified a PPAR-target gene encoding a novel mitochondrial protein ES1. Preliminary studies revealed that ES1 is a mitochondrial protein interacting with the subunits α and β of ATP synthase F1 sector. ES1 appears to be an enhancer of ATP production by increasing ATP synthesis and an inhibitor of ATP hydrolysis. However, it remains unknown if ES1 similarly regulates ATP production in the heart. Interestingly, our preliminary studies revealed that ES1 protein levels were decreased in the hearts from 14 month-old mice. Based on the pilot studies on conditional transgenic and gene targeting mouse lines, we hypothesize that ES1 is a novel therapeutic target of protecting the heart from aging-relating cardiomyopathy. To test this central hypothesis, we will first determine whether gene therapy that increasing cardiac ES1 expression will protect the heart from aging-related hypertrophy. We will then define the underlying molecular and biochemical mechanisms by determining the role of ES1 as an endogenous regulator of ATP synthase and as a determinant of mitochondrial structure/function in the heart. We anticipate the proposed study will provide strong evidence supporting that ES1 is a crucial regulator of myocardial energy metabolism via its regulatory effects on the ATP synthase and mitochondrial structure/function. Result of this study will provide preclinical evidence that ES1 can be a new target for protecting the heart from aging related hypertrophy.

线粒体在能量代谢和氧化还原调节中起核心作用。来 过去十年，越来越多的证据表明， 线粒体功能障碍和与各种衰老相关的主要表型 组织，包括心脏。衰老的心脏易发生心肌肥大， 特别是在机械应力如左心室压力超负荷下。 ATP合成酶是线粒体中产生ATP的关键酶复合体， 在线粒体功能中的核心作用。ATP合酶的功能缺陷可导致 加重人类疾病，如心肌病和充血性心力衰竭， 尤其是在人口老龄化的情况下。然而，目前尚不清楚是否受损的线粒体， ATP合酶是能量缺乏的潜在机制之一， 衰老心脏中的线粒体功能障碍我们最近发现了一个PPAR靶点 编码一种新的线粒体蛋白ES 1的基因。初步研究表明，ES 1 是一种与ATP合酶F1的α和β亚基相互作用的线粒体蛋白 部门ES 1似乎是通过增加ATP合成来增强ATP产生的增强剂 和ATP水解抑制剂。然而，它仍然是未知的，如果ES 1类似 调节心脏中ATP的产生。有趣的是，我们的初步研究显示， 14个月大的小鼠心脏中的ES 1蛋白水平降低。基于 在条件转基因和基因打靶小鼠品系的初步研究中， 假设ES 1是一种新治疗靶点， 与衰老有关的心肌病为了验证这个核心假设，我们将首先确定 增加心脏ES 1表达的基因治疗是否会保护心脏免受 与衰老相关的肥大。然后，我们将定义潜在的分子和 通过确定ES 1作为内源性调节因子的作用， ATP合酶和作为心脏中线粒体结构/功能的决定因素。我们 预计拟议的研究将提供强有力的证据，支持ES 1是一个 通过对ATP的调节作用，是心肌能量代谢的重要调节剂 合成酶和线粒体结构/功能。本研究的结果将提供临床前 有证据表明，ES 1可以成为保护心脏免受衰老相关疾病影响的新靶点。 肥厚