Methylarginines and Vascular Injury

甲基精氨酸和血管损伤

• 批准号: 7992541
• 负责人: Arturo J Cardounel
• 金额: $ 4.25万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-03-15 至 2010-08-05
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7992541
• 关键词: Affect; American; Amino Acids; Anabolism; Animal Model; Antiatherogenic; Arginine; Atherosclerosis; Biological Markers; Blood Vessels; Cardiovascular Diseases; Cell physiology; Citrulline; Clinical Research; DNA; Development; Disease; Endothelium; Enzymes; Functional disorder; Generations; Genetic Transcription; Goals; Grant; Homeostasis; Hydrolase; Impairment; In Vitro; Injury; Laboratories; Lead; Mediating; Metabolic; Metabolism; Methylation; Molecular; Morbidity - disease rate; N,N-dimethylarginine; Nitric Oxide; Nitric Oxide Synthase; Pathogenesis; Pathology; Pathway interactions; Pharmaceutical Preparations; Physiological; Plasma; Play; Post-Translational Protein Processing; Production; Protein-Arginine N-Methyltransferase; Proteins; Proteolysis; Public Health; Quality of life; Regulation; Research; Research Support; Role; Signal Transduction; Testing; Transferase; Vascular Diseases; Vasodilator Agents; dimethylarginine; enzyme activity; improved; in vivo Model; inhibitor/antagonist; insight; mortality; novel; novel strategies; protein B; protein function; public health relevance; therapeutic target

DESCRIPTION (provided by applicant): The long term objective of this proposal is to establish Protein Arginine Methyltransferases and Dimethyarginine Dimethylaminohydrolase (DDAH), the enzymes responsible for methylarginine synthesis and metabolism, as a key regulator of endothelial function. It is our hypothesis that the increased plasma ADMA observed in cardiovascular disease is a biomarker of DDAH activity and that many of the endothelial affects attributed to ADMA are directly manifested through altered DDAH-PRMT activity. We have shown that in addition to the direct effects of ADMA on eNOS activity, DDAH modulates endothelial NO production through ADMA independent mechanisms involving altered protein-methylation and amino acid metabolism. The goals of the current proposal are to: 1) identify the pathways of ADMA metabolism in the endothelium; 2.) determine the mechanisms through which DDAH modulates endothelial protein-arginine methylation and define the effects of protein methylation on endothelial function; 3.) determine the mechanisms through which DDAH regulates endothelial L-arginine metabolism and the consequences on endothelial NO production; and 4.) identify the mechanisms through which the PRMT-DDAH-ADMA axis regulates endothelial function and atherosusceptibility. For each of these aims, a combination of cellular, molecular, biophysical and physiological approaches will be used to characterize the effects of DDAH on endothelial function using in vitro and in vivo models. Results from these studies will provide fundamental mechanistic information regarding the mechanisms through which the PRMT-DDAH-ADMA axis modulates cellular function and may lead to new approaches to treat vascular disease. PUBLIC HEALTH RELEVANCE: This research is relevant to public health since atherosclerosis is among the leading cause morbidity and mortality in Americans. Our research has discovered new cellular pathways that are involved in the development of vascular diseases. Research supported by this grant may help identify new drugs to treat arterial pathology and could improve the quality of life of people suffering from cardiovascular disease.

描述（由申请人提供）：本提案的长期目标是建立蛋白精氨酸甲基转移酶和二甲基精氨酸二甲氨基水解酶（DDAH），这两种酶负责甲基精氨酸的合成和代谢，作为内皮功能的关键调节因子。我们的假设是，在心血管疾病中观察到的血浆ADMA升高是DDAH活性的生物标志物，许多归因于ADMA的内皮影响直接表现为DDAH- prmt活性的改变。我们已经证明，除了ADMA对eNOS活性的直接影响外，DDAH还通过ADMA独立的机制调节内皮细胞NO的产生，包括改变蛋白质甲基化和氨基酸代谢。本课题的目标是：1)确定ADMA在内皮细胞中的代谢途径；2.)确定DDAH调节内皮蛋白精氨酸甲基化的机制，明确蛋白甲基化对内皮功能的影响；3)确定DDAH调节内皮细胞l -精氨酸代谢的机制及其对内皮细胞NO生成的影响；4)确定PRMT-DDAH-ADMA轴调节内皮功能和动脉粥样硬化易感性的机制。为了实现这些目标，我们将结合细胞、分子、生物物理和生理方法，在体外和体内模型中描述DDAH对内皮功能的影响。这些研究的结果将提供关于PRMT-DDAH-ADMA轴调节细胞功能的机制的基本机制信息，并可能导致治疗血管疾病的新方法。