The role of PON2 and PON3 proteins in atherosclerosis

PON2和PON3蛋白在动脉粥样硬化中的作用

基本信息

批准号：
8703745
负责人：
SRINIVASA T. Reddy
金额：
$ 37.73万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-01-01 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8703745
关键词：
Adenoviruses Affect Affinity Alzheimer&apos s Disease Anti-Inflammatory Agents Anti-inflammatory Antiatherogenic Antioxidants Apolipoprotein E Apoptosis Atherosclerosis Bile Acids Binding Biological Blood Vessels Cardiovascular Diseases Cell physiology Cells Coenzyme Q10 Complex Complication Complications of Diabetes Mellitus Conditioned Culture Media Development Diabetes Mellitus Diet Disease Endothelial Cells Enzymes Epidemiologic Studies Etiology Family Gene Duplication Gene Family Genes Genetic Polymorphism Gluconolactonase Goals Health Hepatic High Density Lipoproteins Human In Vitro Infection Inflammation Inflammatory Insulin Resistance Knockout Mice Laboratories Lesion Lipid Peroxidation Lipids Lipoproteins Malignant Neoplasms Mediating Membrane Metabolism Mitochondria Molecular Molecular Target Mus Myocardial Ischemia Obesity Oligomycins Orphan Oxidative Stress Oxygen Consumption Parkinson Disease Pathogenesis Pathology Pathway interactions Phospholipids Physiological Play Predisposition Production Property Proteins Publishing Reporting Role Sequence Analysis Stress Superoxides Time Tissues Toxicology Transgenic Mice Work antimycin aryldialkylphosphatase base enzyme activity esterase extracellular impaired glucose tolerance in vivo insulin signaling lipid metabolism lipid transport macrophage member metabolomics mitochondrial dysfunction mouse model new therapeutic target novel overexpression oxidation particle prevent protein function

项目摘要

DESCRIPTION (provided by applicant): Paraoxonases (PON), a family of orphan enzymes with multiple enzyme activities assigned to them, comprise of three proteins PON1, PON2, and PON3. The aryl esterase, organophosphatase, and lipo-lactonase activities of PON enzymes underscore their importance in inflammation, toxicology, and infection, respectively. Epidemiological studies identified PON proteins in the etiology of a number of inflammatory diseases including cardiovascular diseases. Sequence analysis of PON genes suggest that the PON family evolved by gene duplication with PON2 being the first and PON1 the most recent member. Interestingly, PON2 and PON3 are predominantly localized to intracellular compartments while PON1 is found exclusively extracellular and associated solely with HDL particles. Our laboratory has cloned and characterized both PON2 and PON3 genes, and also developed mouse models for studying the role of PON2 and PON3 in atherosclerosis. Recent studies suggest that PON2 and PON3 are associated with mitochondria and mitochondrial associated membranes and play important roles in the modulation of mitochondrial oxidative stress. PON2 protects against the development of atherosclerosis and insulin resistance. Moreover, macrophage PON2 plays a critical role in the mechanisms that mediate both the development of atherosclerosis and insulin resistance. PON3 protects against the development of atherosclerosis and obesity. Despite the role of PON2 and PON3 in critical cellular functions and associated pathologies, the physiological substrates and molecular mechanisms by which PON2 and PON3 function as anti-atherogenic and anti-inflammatory proteins are largely unknown. In this application, we propose to i. delineate the physiological substrates for PON2 and PON3 proteins, ii. determine the molecular mechanisms by which PON2 and PON3 function, and iii. to examine the role of PON2 and PON3 proteins in vascular inflammatory diseases including diabetes, obesity, and ischemic heart disease. These studies will help identify novel molecular targets for the treatment of inflammatory diseases

描述（由申请人提供）：二氧蛋白酶（PON），一个分配给它们的具有多种酶活性的孤儿酶家族，包括三种蛋白质PON1，PON2和PON3。 PON酶的芳基酯酶，有机磷酸酶和脂肪 - 内乳酶活性分别强调了它们在炎症，毒理学和感染中的重要性。流行病学研究确定了许多包括心血管疾病在内的炎症性疾病的病因中的PON蛋白。 PON基因的序列分析表明，PON家族通过基因重复而演变为PON2，而PON1是最新成员。有趣的是，PON2和PON3主要定位于细胞内室，而PON1仅在细胞外，仅与HDL颗粒相关。我们的实验室已经克隆并表征了PON2和PON3基因，还开发了研究PON2和PON3在动脉粥样硬化中的作用的小鼠模型。最近的研究表明，PON2和PON3与线粒体和线粒体相关膜有关，并在线粒体氧化应激的调节中起重要作用。 PON2可以防止动脉粥样硬化和胰岛素抵抗的发展。此外，巨噬细胞PON2在介导动脉粥样硬化和胰岛素抵抗的机制中起着至关重要的作用。 PON3可以防止动脉粥样硬化和肥胖的发展。尽管PON2和PON3在关键细胞功能和相关病理学中的作用，但生理底物和分子机制，PON2和PON3用作抗动脉粥样硬化和抗炎症蛋白的作用在很大程度上是未知的。在此应用程序中，我们向i提出建议。描述PON2和PON3蛋白的生理底物，II。确定PON2和PON3功能以及III的分子机制。检查PON2和PON3蛋白在包括糖尿病，肥胖和缺血性心脏病在内的血管炎症性疾病中的作用。这些研究将有助于确定用于治疗炎症性疾病的新型分子靶标