Restore energy capacity in the aging heart

恢复衰老心脏的能量容量

基本信息

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
项目类别：
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

项目摘要

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发挥着核心作用。过去十年，越来越多的证据表明，两者之间存在因果关系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，老化的心脏会出现心脏肥大，尤其是在机械应力下，例如左心室压力超负荷时。 ATP合酶是线粒体中产生ATP的关键酶复合物，因此发挥着 ATP合酶的功能缺陷可导致线粒体功能的核心作用。加重人类疾病，如心肌病和充血性心力衰竭，特别是在老龄化人群中，然而，目前尚不清楚线粒体是否受损。 ATP合酶是能量缺乏的潜在机制之一我们最近发现了一个 PPAR 靶点。初步研究表明，编码一种新型线粒体蛋白ES1的基因。是一种与 ATP 合酶 F1 的 α 和 β 亚基相互作用的线粒体蛋白 ES1 似乎是通过增加 ATP 合成来增强 ATP 的产生。和 ATP 水解抑制剂然而，ES1 是否具有类似作用仍不清楚。我们的初步研究表明，它可以暗示性地调节心脏中 ATP 的产生。 14 个月大的小鼠心脏中 ES1 蛋白水平下降。对条件转基因和基因靶向小鼠品系的初步研究，我们 ES1 是保护心脏免受损害的新治疗靶点为了检验这一中心假设，我们首先确定与衰老相关的心肌病。增加心脏 ES1 表达的基因治疗是否可以保护心脏免受然后我们将定义与衰老相关的肥大的潜在分子和机制。通过确定 ES1 作为内源性调节因子的作用来研究生化机制 ATP 合酶并作为心脏线粒体结构/功能的决定因素。预计拟议的研究将提供强有力的证据支持 ES1 是通过对 ATP 的调节作用，成为心肌能量代谢的重要调节者这项研究的结果将提供临床前研究。有证据表明 ES1 可以成为保护心脏免受衰老相关影响的新靶点肥大。