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

基本信息

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
项目类别：
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

项目摘要

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。