The role of PON2 and PON3 proteins in atherosclerosis

描述(由申请人提供)：对氧磷酶(PON)是一个具有多种酶活性的孤儿酶家族，由三种蛋白PON1、PON2和PON3组成。PON酶的芳基酯酶、有机磷酸酶和脂乳糖酶活性分别强调了它们在炎症、毒理学和感染中的重要性。流行病学研究发现PON蛋白在包括心血管疾病在内的许多炎症性疾病的病因学中起作用。PON基因的序列分析表明，PON家族是通过基因复制进化而来的，PON是第一个基因，PON1是最近的成员。有趣的是，PON2和PON3主要定位于细胞内的隔室，而PON1仅发现在细胞外，仅与高密度脂蛋白颗粒有关。本实验室已克隆并鉴定了PON_2和PON_3基因，并建立了研究PON_2和PON_3在动脉粥样硬化中作用的小鼠模型。最近的研究表明，PON_2和PON_3与线粒体和线粒体相关膜有关，在线粒体氧化应激的调控中发挥重要作用。PON2可预防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发展的机制中起着关键作用。PON3可以预防动脉粥样硬化和肥胖的发生。尽管PON2和PON3在重要的细胞功能和相关的病理过程中发挥作用，但PON2和PON3作为抗动脉粥样硬化和抗炎蛋白发挥作用的生理底物和分子机制尚不清楚。在这个应用中，我们建议I.描述PON2和PON3蛋白的生理底物，II.确定PON2和PON3发挥作用的分子机制，以及研究PON2和PON3蛋白在糖尿病、肥胖和缺血性心脏病等血管炎症性疾病中的作用。这些研究将有助于确定治疗炎症性疾病的新分子靶点。

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