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：改善经济和繁荣的主要弊端之一是糖尿病 - 细胞的兴起。久坐的生活方式和高热量饮食与糖尿病的兴起有关。糖尿病患者处于患心肌病和心力衰竭（HF）的高风险。这样的患者也经历了最坏的临床结果以下，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。但是，这种疾病过程的基本机制尚未完全理解，没有针对性的疗法可用于治疗糖尿病心肌病。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在糖尿病性心肌病后保护心脏免于降低到衰竭。我的实验室有特定的利益在Sirtuins（Sirts）中，它们是众多生物功能的关键调节剂，跨越细胞增长，差异与寿命。我们实验室的最新工作已经确定了SIRT6，作为内源性心脏肥大的阴性调节剂。在糖尿病心脏中，我们发现SIRT6水平急剧减少；这与纤维化激活剂的表达增加相似，炎症体形成和胰岛素抵抗。我们还发现SIRT6缺乏导致基因表达降低维持线粒体的结构和功能。这些发现导致我们假设Sirt减少了6 水平有助于糖尿病心肌病和随后的HF进化。因此，糖尿病心脏可以通过增加心脏SIRT6水平来保护免于降至HF。我们将在以下三个目标：（目标1）研究SIRT6的丧失是否有助于与病理变化有关随着糖尿病心肌病的演变，以及SIRT6过表达的转基因小鼠是否是免受糖尿病后HF的保护。（AIM 2）研究SIRT6缺乏症的潜在机制在糖尿病期间以及SIRT6维持线粒体健康的机制并保护心脏发展疾病。（AIM 3）研究SIRT6的药理学靶向6是否可以保护患有糖尿病心肌病和HF的心脏。完成这些目标而获得的知识了解Sirtuins在糖尿病心肌病的发病机理中扮演着什么角色非常重要，这可能与开发用于糖尿病患者HF治疗的新疗法有关。