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: 10649534
• 负责人: Robert Walker McGarrah
• 金额: $ 52.47万
• 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/10649534
• 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; 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; Oxidoreductase; Pathway interactions; Perfusion; Phenotype; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Physiological; Physiology; Plasma; Protein Biosynthesis; Proteins; Regional Perfusion; Role; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Site; Structure; Techniques; Tissues; Valine; Work; branched chain alpha ketoacid dehydrogenase; comparison control; flexibility; genetic approach; heart function; in vivo; insight; metabolic phenotype; mortality; mouse model; novel; novel therapeutic intervention; oxidation; pandemic disease; pharmacologic; 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.

肥胖、糖尿病和心力衰竭等心脏代谢疾病状态的一个新特征受到干扰 血浆支链氨基酸（BCAA；缬氨酸、亮氨酸、 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已经揭示 由于支链 α-酮酸活性受损，在这些情况下会出现血浆 BCKA 升高 肝脏中的脱氢酶 (BCKDH) 复合物，由抑制性 BCKDH 激酶的较高表达引起， BDK，以及激活磷酸酶 PPM1K 的较低表达。重要的是，全身操纵 通过 BDK 和 PPM1K 的药理或基因调节实现 BCKA 代谢，产生强大的影响 心脏的结构、功能和代谢。因此，针对 BCKA 相关的新治疗方法 途径在治疗心功能障碍方面具有巨大潜力。但目前尚不清楚是否 全身 BDK 和 PPM1K 操作对心脏功能的体内影响是由于调节 心脏内的 PPM1K 和 BDK 活性或仅仅是心脏长期暴露在增加的环境中的结果 血浆BCKA。本提案中概述的工作将建立在我们之前的工作基础上，以直接解决这一重要问题 通过利用新开发的动物模型来弥补知识差距：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 介导的信号转导机制的理解 心中的路径； 3) 定义 PPM1K 在心脏中的作用。完成后获得的知识 该项目预计将有助于开发用于治疗心脏病的 BCKA 相关治疗靶点 多种心脏代谢疾病的功能障碍。