Roles of NAD+ metabolism in diabetic cardiomyopathy

NAD代谢在糖尿病心肌病中的作用

• 批准号: 10339351
• 负责人: Chi Fung Lee
• 金额: $ 34.96万
• 依托单位: OKLAHOMA MEDICAL RESEARCH FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-05 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10339351
• 关键词: Acetylation; Affect; Arginine; Calcium; Cardiac; Cardiac Myocytes; Cardiac health; Catabolism; Cause of Death; Cell physiology; Consumption; Data; Dependovirus; Diabetes Mellitus; Diabetic mouse; Enzymes; Epidemic; Event; Family; Fatty Acids; Fibrosis; Functional disorder; Genes; Glucose; Glutamine; Goals; Heart; Heart failure; Homeostasis; In Vitro; Investigation; Kinetics; Laboratories; Lead; Length; Link; Literature; Lysine; Measurement; Mediating; Messenger RNA; Metabolic Control; Metabolism; Mission; Mitochondria; Modification; Molecular; Mus; Myocardial dysfunction; NADH; Oklahoma; Oxidation-Reduction; Oxygen Consumption; Pathogenicity; Pathway interactions; Permeability; Phosphorylation; Phosphotransferases; Pilot Projects; Protein Array; Proteins; Reaction; Research; Risk Factors; Role; Sarcomeres; Sirtuins; Site; Stress; Testing; Transcript; Treatment Protocols; Type 2 diabetic; Up-Regulation; Variant; calmodulin-dependent protein kinase II; cofactor; diabetic; diabetic cardiomyopathy; diabetic patient; functional decline; heart function; in vivo; mimetics; mouse model; mutant; new therapeutic target; nicotinamide-beta-riboside; overexpression; pressure; release of sequestered calcium ion into cytoplasm; response; type I diabetic

Diabetes is one of the major risk factors of heart failure and is characterized by a loss of metabolic control. Heart failure is the main cause of death for diabetic patients. Literature and pilot studies support that NAD+ redox imbalance promotes diabetic cardiomyopathy. However, mechanisms by which altered NAD+ metabolism contributes to diabetic cardiomyopathy are far from established. This project aims to dissect how diabetic stress alters NAD+ metabolism, and in turn promotes cardiac dysfunction. Our pilot studies show that up-regulated nicotinamide riboside kinase (NMRK) could be a pathogenic mechanism of altered NAD+ metabolism in diabetic hearts. In Aim 1, we will use targeted analyses of metabolites and transcripts involved in NAD+ metabolism to determine how NMRK up-regulation regulates NAD+ metabolism in cardiomyocytes. We will determine the pathogenic significance of NMRK up-regulation to the progression of diabetic cardiomyopathy using adeno- associated virus-mediated over-expression in diabetic mice. Our pilot data identify that acetylation of calmodulin- dependent protein kinase II (CaMKII), a key kinase regulating heart function, may contribute to diabetic cardiomyopathy. In Aim 2, we will over-express acetylation mutants, and test the hypothesis that acetylation of CaMKII regulates cardiomyocyte and mitochondrial function in vitro, and diabetic cardiomyopathy in vivo. This project will explore an emerging paradigm that NAD+ metabolism regulates diabetic cardiomyopathy. The long- term goal is to identify new therapeutic targets to treat cardiac dysfunction induced by diabetes, especially for diastolic dysfunction that is a growing epidemic, and has no specific treatment regimen.

糖尿病是心力衰竭的主要危险因素之一，其特征是代谢控制的丧失。心