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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以舒张功能障碍为特征的心力衰竭的独立危险因素和左心室肥厚。糖尿病心肌病的特点是心肌细胞燃料的显着变化代谢，促进向高级病理状态的转变。燃料代谢的改变包括增加对脂肪酸氧化来产生机械能的依赖，而以牺牲其他物质为代价底物如葡萄糖。由此产生的代谢灵活性的丧失会导致心脏做功减少效率和收缩功能障碍。驱动燃料底物利用率变化的细胞机制尚未得到充分理解，这一缺陷是小说发展的主要障碍治疗。在这项提案中，我们的目标是研究一种新型肽 - 阿德洛宾 - 逆转燃料的效用糖尿病心肌病中观察到的代谢缺陷。在目标 1 中，我们将研究 adropin 对调节心脏葡萄糖氧化的新细胞途径。在目标 2 中，我们将检查所扮演的角色通过adropin信号通路调节线粒体燃料代谢。在目标 3 中，我们将检查是否 adropin 是临床前动物模型中治疗糖尿病心肌病的候选分子。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，并将强调这种疾病的潜在新治疗途径。