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Exploring roles of sirtuins in protecting diabetic hearts

探索去乙酰化酶在保护糖尿病心脏中的作用

基本信息

批准号：
10214667
负责人：
MAHESH P GUPTA
金额：
$ 46.83万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-15 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10214667
关键词：
Acetylation Age Animal Model Animals Biological Process Caloric Restriction Calories Cardiac Cardiac Surgery procedures Cardiomyopathies Cardiovascular Diseases Cause of Death Cell Nucleus Cells Clinical Clinical Research Consensus Coupled Deacetylase Dependence Development Diabetes Mellitus Diabetic mouse Diet Disease Disease Progression Down-Regulation Enzymes Evolution Exercise FRAP1 gene Failure Family Fatty acid glycerol esters Fibrosis Frequencies Functional disorder Gene Expression Genetic Transcription Health Health Benefit Heart Heart Diseases Heart Hypertrophy Heart failure Human Hypertension Industrialization Inflammasome Inflammation Insulin Resistance Intervention Knowledge Laboratories Ligation Longevity MAPK8 gene Mitochondria Molecular Mus Myocardial Infarction NF-kappa B Nonesterified Fatty Acids Outcome Oxidative Stress Pathogenesis Pathologic Pathway interactions Patients Pharmacology Phosphorylation Play Prevalence Process Protein Isoforms Proteomics Reporting Risk Factors Role SIRT1 gene Signal Transduction Sirtuins Stress Structure Sucrose Testing Time Transgenic Mice Woman Work analog base cell growth chromatin remodeling coronary fibrosis design diabetic diabetic cardiomyopathy diabetic patient experience fatty acid oxidation high risk improved induced pluripotent stem cell interest mammalian genome men mitochondrial dysfunction novel strategies novel therapeutic intervention novel therapeutics overexpression pressure response screening sedentary lifestyle small molecule libraries targeted treatment therapeutic target transcriptome sequencing western diet

项目摘要

Summary: One of the major downsides of improved economy and prosperity is the rise of diabetes-mellitus. Sedentary life-style and high calorie diet are implicated in the rise of diabetes. Patients with diabetes are at high risk of developing cardiomyopathy and heart failure (HF). Such patients also experience worst clinical outcome following, hypertension, myocardial infarction and cardiac surgery. At the cellular level, increased inflammation, insulin-resistance, cardiac hypertrophy and fibrosis are considered hallmarks of diabetic cardiomyopathy. However, the underlying mechanism of this disease process is not yet completely understood, and no targeted therapy is available to treat diabetic cardiomyopathy. New approaches are needed to understand the mechanism behind this disease, and to identify new therapeutic strategies to protect the heart from descending to failure post diabetic cardiomyopathy. My laboratory has specific interests in sirtuins (SIRTs), which are emerging as key regulators of myriad of biological functions, spanning from cell growth, differentiation to longevity. Recent work from our laboratory has identified SIRT6, as an endogenous negative regulator of cardiac hypertrophy. In diabetic hearts, we found that SIRT6 levels were drastically reduced; and this was paralleled with increased expression of activators of fibrosis, inflammasome formation and insulin-resistance. We also found that SIRT6 deficiency leads to decreased expression of genes needed to maintain structure and function of mitochondria. These findings led us to hypothesize that decreased SIRT6 levels contribute to the evolution of diabetic cardiomyopathy and subsequent HF. Therefore, a diabetic heart can be protected from descending to HF by augmenting cardiac SIRT6 levels. We will test this hypothesis in the following three aims: (Aim 1) Study whether loss of SIRT6 contributes to pathologic changes associated with the evolution of diabetic cardiomyopathy, and whether SIRT6 overexpressing transgenic mice are protected from developing HF post diabetes. (Aim 2) Study the underlying mechanism of SIRT6 deficiency during diabetes, and the mechanism through which SIRT6 maintains mitochondrial health and protects the heart from developing the disease. (Aim 3) Study whether pharmacological targeting of SIRT6 can protect the heart from developing diabetic cardiomyopathy and HF. The knowledge gained from completing these aims will be extremely important to understand what roles sirtuins play in pathogenesis of diabetic cardiomyopathy, and that could be pertinent to developing new therapies for treatment of HF in diabetic patients.

摘要：经济和繁荣改善的主要缺点之一是糖尿病的增加。久坐的生活方式和高热量饮食与糖尿病的增加有关。糖尿病患者处于患心肌病和心力衰竭（HF）的风险很高。此类患者也会经历最糟糕的临床症状结果如下：高血压、心肌梗塞和心脏手术。在细胞水平上，增加炎症、胰岛素抵抗、心脏肥大和纤维化被认为是糖尿病的标志心肌病。然而，这种疾病过程的潜在机制尚未完全阐明。据了解，目前尚无治疗糖尿病心肌病的靶向疗法。新方法是需要了解这种疾病背后的机制，并确定新的治疗策略保护心脏免于糖尿病心肌病后下降至衰竭。我的实验室有特定的兴趣去乙酰化酶 (SIRT) 正在成为从细胞到细胞的无数生物功能的关键调节因子生长、分化、长寿。我们实验室最近的工作已确定 SIRT6 是一种内源性心脏肥大的负调节剂。在糖尿病心脏中，我们发现 SIRT6 水平急剧下降减少；这与纤维化激活剂表达增加、炎性小体形成同时发生和胰岛素抵抗。我们还发现 SIRT6 缺陷会导致所需基因的表达减少维持线粒体的结构和功能。这些发现使我们推测 SIRT6 减少水平有助于糖尿病心肌病和随后的心力衰竭的发展。因此，糖尿病心脏可以通过提高心脏 SIRT6 水平来防止下降为心力衰竭。我们将在以下三个目标：（目标 1）研究 SIRT6 的缺失是否会导致相关的病理变化随着糖尿病心肌病的演变，SIRT6过表达转基因小鼠是否预防糖尿病后发生心力衰竭。（目标2）研究SIRT6缺陷的潜在机制糖尿病期间 SIRT6 维持线粒体健康并保护线粒体的机制心脏免于患病。（目标3）研究SIRT6的药理学靶向是否可以保护心脏免受糖尿病性心肌病和心力衰竭的影响。从完成这些目标中获得的知识了解去乙酰化酶在糖尿病心肌病发病机制中的作用极其重要，这可能与开发治疗糖尿病患者心力衰竭的新疗法有关。