Mechanisms Connecting Dysregulated Branched-Chain Alpha-Ketoacid Metabolism to Cardiac Dysfunction

支链α-酮酸代谢失调与心脏功能障碍的机制

• 批准号: 10517213
• 负责人: Robert Walker McGarrah
• 金额: $ 52.15万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10517213
• 关键词: Acute; Address; Animal Model; Branched-Chain Amino Acids; Cardiac; Cardiometabolic Disease; Catabolism; Chronic; Citric Acid Cycle; Complex; Data; Development; Diabetes Mellitus; Disease; Down-Regulation; EFRAC; Enzymes; Epidemic; Exposure to; FRAP1 gene; Failure; Genetic; Goals; Heart; Heart failure; Impairment; Insulin Resistance; Isoleucine; Keto Acids; Knockout Mice; Knowledge; Leucine; Liver; MAP Kinase Gene; MAPK3 gene; Mediating; Metabolic; Metabolic Diseases; Metabolism; Mitochondria; Modeling; Morbidity - disease rate; Mus; Myocardial dysfunction; Myocardium; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pathway interactions; Perfusion; Pharmacology; Phenotype; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Physiological; Physiology; Plasma; Protein Biosynthesis; Proteins; Role; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Site; Structure; Techniques; Tissues; Valine; Work; branched chain alpha ketoacid dehydrogenase; genetic approach; heart function; in vivo; insight; metabolic phenotype; mortality; mouse model; novel; novel therapeutic intervention; oxidation; pandemic disease; preservation; pressure; stable isotope; therapeutic target; transamination

An emerging feature of cardiometabolic disease states, including obesity, diabetes, and heart failure is perturbed metabolism and subsequent elevations of plasma branched-chain amino acids (BCAA; valine, leucine, isoleucine) and their cognate α-ketoacids (BCKA; KIV, KIC, KMV). Work from our group and others has revealed that elevated plasma BCKA arise in these conditions due to impaired activity of the branched chain a-ketoacid dehydrogenase (BCKDH) complex in liver, resulting from higher expression of the inhibitory BCKDH kinase, BDK, and lower expression of the activating phosphatase, PPM1K. Importantly, whole-body manipulation of BCKA metabolism achieved via pharmacologic or genetic modulation of BDK and PPM1K yields robust impacts on cardiac structure, function, and metabolism. Thus, novel therapeutic approaches targeting BCKA-related pathways hold significant potential for treatment of cardiac dysfunction. However, it remains unclear whether the in vivo effects of systemic BDK and PPM1K manipulation on cardiac function are due to modulation of PPM1K and BDK activity within the heart or simply the result of chronic exposure of the heart to increased plasma BCKA. The work outlined in this proposal will build upon our prior work to directly address this important knowledge gap by leveraging newly developed animal models to: 1) Determine the impact of liver-specific BDK modulation on cardiac function; 2) Extend our mechanistic understanding of BCKA-mediated signal transduction pathways in the heart; and 3) Define the role of PPM1K in the heart. The knowledge gained from the completion of this project is expected to aid in development of BCKA-related therapeutic targets for the treatment of cardiac dysfunction in a wide range of cardiometabolic diseases.

心脏代谢疾病状态的新兴特征，包括肥胖，糖尿病和心力衰竭 血浆分支链氨基酸的代谢和随后的升高（BCAA； Valine，Leucine， 异亮氨酸）及其同源α-酮酸（BCKA； KIV，KIC，KMV）。我们小组和其他人的工作揭示了 由于分支链A-KetoAcid的活性受损，在这些条件下，血浆BCKA升高出现 肝脏中的脱氢酶（BCKDH）复合物，是由于抑制性BCKDH激酶的较高表达引起的 BDK和激活磷酸酶的较低表达PPM1K。重要的是，全身操纵 通过BDK和PPM1K的药物或遗传调制实现的BCKA代谢产生了强大的影响 关于心脏结构，功能和代谢。那是针对BCKA相关的新型治疗方法 途径对心脏功能障碍的治疗具有巨大的潜力。但是，尚不清楚是否 全身BDK和PPM1K操纵对心脏功能的体内影响是由于调节 ppm1k和BDK活性在心脏内或心脏长期暴露导致增加的结果 等离子体BCKA。本提案中概述的工作将以我们先前的工作为基础，直接解决这一重要的事情 通过利用新开发的动物模型的知识差距：1）确定肝脏特异性BDK的影响 对心脏功能的调节； 2）扩展我们对BCKA介导的信号传输的机械理解 心脏中的道路； 3）定义ppm1k在心脏中的作用。从完成中获得的知识 预计该项目有助于开发与心脏治疗的BCKA相关治疗靶标 多种心脏代谢疾病的功能障碍。