Novel strategies to resolve metabolic defects in the diabetic heart

解决糖尿病心脏代谢缺陷的新策略

基本信息

批准号：
10592286
负责人：
Iain Scott
金额：
$ 47.9万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10592286
关键词：
Ablation Acetylation Acetyltransferase Address Advanced Development Animal Model Animals Biochemical Bioenergetics Brain Cardiac Cardiac Myocytes Cells Clinical Cultured Cells Data Defect Development Diabetic mouse Disease Enzymes Exhibits Functional disorder Future G-Protein-Coupled Receptors Glucose Goals Heart Heart Diseases Heart failure High Fat Diet Impairment In Vitro Incidence Insulin Intervention Knockout Mice Left Ventricular Hypertrophy Link Liver Measurement Mediating Metabolic Metabolic dysfunction Metabolism Mitochondria Modeling Molecular Molecular Target Mus Nonesterified Fatty Acids Obesity Orphan Output Pathologic Pathway interactions Peptides Peripheral Play Prediabetes syndrome Production Proteins Regulation Research Risk Factors Role Signal Pathway Signal Transduction Source Stress Testing Time Tissues Work analog blood glucose regulation diabetic diabetic cardiomyopathy diabetic patient diabetogenic dietary control fatty acid oxidation flexibility functional decline heart function heart metabolism improved in vivo knock-down mechanical energy novel novel strategies oxidation peptide hormone pre-clinical pyruvate dehydrogenase receptor small molecule tool transmission process

项目摘要

ABSTRACT Diabetic cardiomyopathy is an independent risk factor for heart failure characterized by diastolic dysfunction and left ventricular hypertrophy. Diabetic cardiomyopathy features striking changes in cardiomyocyte fuel metabolism, which promote the transition into an advanced pathological state. Alterations in fuel metabolism include an increased reliance on fatty acid oxidation for mechanical energy production, at the expense of other substrates such as glucose. The resultant loss of metabolic flexibility can result in reduced cardiac work efficiency and contractile dysfunction. The cellular mechanisms that drive changes in fuel substrate utilization are not fully understood, and this deficiency represents a major impediment to the development of novel treatments. In this proposal, we aim to investigate the utility of a novel peptide – adropin – to reverse the fuel metabolism defects observed in diabetic cardiomyopathy. In Aim 1, we will investigate the effects of adropin on novel cellular pathways that regulate glucose oxidation in the heart. In Aim 2, we will examine the role played by adropin signaling pathways in regulating mitochondrial fuel metabolism. In Aim 3, we will examine whether adropin is a candidate molecule for diabetic cardiomyopathy treatment in pre-clinical animal models. It is expected that these studies will elucidate new cellular pathways that are central to the metabolic dysfunction observed in diabetic cardiomyopathy, and will highlight potential new treatment pathways for this disorder.

抽象的糖尿病心肌病是舒张功能障碍的心力衰竭的独立危险因素并左心室肥大。糖尿病心肌病具有心肌细胞燃料的引人注目的变化代谢，促进过渡到晚期病理状态。燃料代谢的改变包括增加脂肪酸氧化的机械能量生产的缓解，以其他诸如葡萄糖之类的底物。代谢柔韧性的导致丧失会导致心脏工作减少效率和收缩功能障碍。驱动燃料基材利用率变化的细胞机制尚未完全理解，这种缺陷代表了新颖的发展的主要障碍治疗。在此提案中，我们旨在调查一种新型肽（adropin）的效用，以扭转燃料糖尿病心肌病中观察到的代谢缺陷。在AIM 1中，我们将研究adropin的影响调节心脏中葡萄糖氧化的新型细胞途径。在AIM 2中，我们将研究扮演的角色通过调节线粒体燃料代谢中的Adropin信号通路。在AIM 3中，我们将检查是否 Adropin是临床前动物模型中糖尿病心肌病治疗的候选分子。这是预计这些研究将阐明对代谢功能障碍至关重要的新细胞途径在糖尿病心肌病中观察到，并将突出该疾病的潜在新治疗途径。