PON2 and PON3 proteins in Atherosclerosis

描述（由申请方提供）：在人类和动物模型中的许多病理生理学观察结果导致以下假设：动脉粥样硬化（一种大动脉疾病，是冠心病（CHD）和卒中的主要原因）是一种多因素慢性炎症性疾病，其中低血浆HDL水平和高血浆LDL水平是该疾病的强预测因子。LDL氧化被认为是动脉粥样硬化病变发展的重要过程。氧化LDL的促炎成分是由氧化不饱和脂肪酸的断裂和重排产生的各种氧化磷脂。HDL和HDL相关酶具有抗动脉粥样硬化性质，部分原因是它们使氧化LDL失活。尽管遗传和生物化学研究表明对氧杂环己烷酶-1（PON 1）（HDL相关蛋白）具有抗动脉粥样硬化的作用，但迄今为止，PON家族蛋白（PON 1、PON 2和PON 3）的生理功能仍不清楚。基于我们的初步研究结果，我们假设PON 2和PON 3蛋白抑制LDL中氧化磷脂的积累，保护动脉壁细胞免受活性氧（ROS）和氧化磷脂的氧化应激，并防止动脉粥样硬化病变的发展。在本申请中，我们提出i）表征PON 2和PON 3蛋白的生物化学和酶性质，ii）确定在HDL和高胆固醇血症动物模型中PON 2和PON 3蛋白的细胞定位、酶活性产物和表达水平，（三）开发转基因小鼠和基因敲除小鼠，以确定PON 2和PON 3蛋白的生理功能以及PON 2和PON 3在动脉粥样硬化，和iv）鉴定和表征与P0 N 2和P0 N 3相互作用的蛋白质以描绘P0 N 2和P0 N 3蛋白质的生物底物。了解PON蛋白的生物学和功能将为发现新的治疗药物铺平道路，以对抗动脉粥样硬化和其他炎症性疾病。

DESCRIPTION (provided by applicant): A number of pathophysiological observations in humans and animal models led to the hypothesis that atherosclerosis, a disease of the large arteries that is the primary cause of coronary heart disease (CHD) and stroke, is a multifactorial chronic inflammatory disease in which low plasma levels of HDL and high plasma levels of LDL, are a strong predictor of the condition. LDL oxidation is considered to be an essential process in the development of atherosclerotic lesions. The pro-inflammatory constituents of oxidized LDL are various oxidized phospholipids resulting from the scission and rearrangement of oxidized, unsaturated fatty acids. HDL and HDL-associated enzymes possess anti-atherogenic properties that are due, in part, to their inactivation of oxidized LDL. Although genetic and biochemical studies demonstrated anti-atherogenic role for paraoxanase-1 (PON1), a HDL associated protein, to date, the physiological functions of PON family of proteins; PON1, PON2 and PON3, remain unknown. Based on our preliminary findings, we hypothesize that PON2 and PON3 proteins inhibit the accumulation of oxidized phospholipids in LDL, protect artery wall cells against oxidative stress from reactive oxygen species (ROS) and oxidized phospholipids, and prevent the development of atherosclerotic lesions. In this application, we propose to i) characterize the biochemical and enzymatic properties of PON2 and PON3 proteins, ii) determine cellular localization, products of enzyme activity and the expression levels of PON2 and PON3 proteins in HDL and hyperchloesterolemic animal models, iii) develop transgenic mice and knockout mice to determine the physiological function of PON2 and PON3 proteins as well as the role of PON2 and PON3 in atherosclerosis, and iv) identify and characterize proteins that interact with PON2 and PON3 to delineate the biological substrates of PON2 and PON3 proteins. Understanding the biology and function of the PON proteins will pave way for the discovery of novel therapeutic agents in the fight against atherosclerosis and other inflammatory diseases.