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Mechanisms of PRMT regulation of pulmonary endothelial cell function

PRMT调节肺内皮细胞功能的机制

基本信息

批准号：
9130380
负责人：
LOUIS G CHICOINE
金额：
$ 37.38万
依托单位：
RESEARCH INST NATIONWIDE CHILDREN'S HOSP
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9130380
关键词：
Acute Address Anabolism Animal Model Arginine Biological Markers Blood Vessels Bronchopulmonary Dysplasia Cardiovascular Diseases Categories Cause of Death Cell physiology Cellular biology Chronic Citrulline Clinical Research Data Development Disease Endothelial Cells Enzymes Event Family Functional disorder Generations Goals Grant Growth Health Homeostasis Human Hydrolase Hypertension Hypoxemia Hypoxia Impairment In Vitro Infant Knock-out Knockout Mice Laboratories Lung Lung diseases Mass Spectrum Analysis Measures Mediating Methylation Modeling Molecular Morbidity - disease rate Mutate Nature Neonatal Nitric Oxide Nitric Oxide Synthetase Inhibitor Outcome Oxidases Pathogenesis Pathology Pathway interactions Patients Phosphorylation Physiological Plasma Play Predisposition Production Protein Methylation Protein-Arginine N-Methyltransferase Proteins Proteolysis Proto-Oncogene Proteins c-akt Pulmonary Hypertension Regulation Research Research Support Risk Factors Role Serum Signal Transduction Site Small Interfering RNA Testing Transferase Vascular Diseases Vascular Endothelial Cell Vasodilator Agents World Health Organization dimethylarginine endothelial dysfunction human disease improved in vivo in vivo Model innovation insight mortality neonatal pulmonary hypertension novel omega-N-Methylarginine overexpression protein protein interaction public health relevance research study response therapeutic target vascular endothelial dysfunction

项目摘要

DESCRIPTION (provided by applicant): The overall objective of this proposal is to identify the role of protein arginine methyltransferases (PRMT), the enzymes responsible for protein-arginine methylation and methylarginine synthesis, in the pathogenesis of chronic hypoxia induced pulmonary endothelial dysfunction as seen in pulmonary vascular disease. Although increased serum levels of asymmetric dimethyl arginine (ADMA), an endogenous inhibitor of nitric oxide synthase, have been identified as an independent risk factor for cardiovascular diseases including those associated with chronic hypoxia-induced pulmonary hypertension (PH), evidence from our laboratory indicates that increased plasma ADMA observed in disease may be a biomarker for changes in PRMT activity and that many of the endothelial effects attributed to ADMA are directly manifested through altered activity of PRMT. In this regard, our preliminary data support our overall hypothesis that in addition to competitive inhibition of eNOS activity by ADMA, modulation of eNOS-NO production occurs through direct protein-methylation events mediated by PRMT. Specifically, we demonstrate that eNOS is a substrate of PRMT and that increased methylation of eNOS protein in response to hypoxia may play a critical role in endothelial dysfunction as measured by decreased NO production. The goals of the current proposal are to: 1) Define the role played by the PRMT in hypoxia induced pulmonary endothelial dysregulation; 2) Identify the mechanism(s) by which the PRMT regulates eNOS activity in hypoxia induced pulmonary endothelial dysfunction; 3) Determine the role of dysregulated PRMT activity in the pathogenesis of hypoxia-induced PH. The aims in this proposal will be accomplished through the use of a combination of cellular, molecular, biophysical, and physiological approaches to characterize the role of the PRMT in endothelial function and its regulation by hypoxia using both in vitro and in vivo models. Results from these studies will provide fundamental mechanistic models through which PRMT modulates endothelial function as well as modulates susceptibility to, and progression of, PH.