The role of PON-2 and PON3 proteins in atherosclerosis

PON-2和PON3蛋白在动脉粥样硬化中的作用

基本信息

批准号：
7462402
负责人：
SRINIVASA T. Reddy
金额：
$ 38.07万
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 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7462402
关键词：
Acute Adenoviruses Alzheimer&apos s Disease Animal Model Antiatherogenic Antioxidants Apolipoprotein E Apolipoproteins B Arterial Fatty Streak Arts Atherogenic Diet Atherosclerosis Bacterial Genes Biological Models Cells Chronic Class Cultured Cells Defect Development Diabetes Mellitus Diet Disease Endothelial Cells Enzymes Event Family member Fatty acid glycerol esters Gene Family Genes Gluconolactonase Goals Gram-Negative Bacteria Gram-Negative Bacterial Infections Grant Hepatocyte Host Defense Human Hydrolysis Immune response In Vitro Infection Inflammation Inflammatory Knock-out Knockout Mice Lactones Lesion Link Lipid Peroxidation Lipids Lipoproteins Low Density Lipoprotein oxidation Malignant Neoplasms Mediating Methodology Molecular Mus Paraoxonase-2 Parkinson Disease Pathogenesis Pathology Pathway interactions Personal Satisfaction Phospholipids Physiological Physiology Play Property Protein Overexpression Proteins Pseudomonas aeruginosa Reporter Research Personnel Risk Factors Role Secondary to Signal Transduction Testing Time Tissue Extracts Transgenic Mice Transgenic Organisms Virulence Virulence Factors Week Work airway epithelium aryldialkylphosphatase atherogenesis density homoserine lactone improved in vivo macrophage male member microbial mouse model novel oxidized low density lipoprotein particle pathogen pathogenic bacteria prevent programs quorum sensing research study sensor

项目摘要

DESCRIPTION (provided by applicant): The paraoxonase (PON) gene family consists of three family members, PON1, PON2 and PONS. PON genes are implicated in the pathogenesis of several inflammatory diseases including atherosclerosis. All three PON proteins possess antioxidant properties and lactonase activities; however, the physiological substrates for PON proteins and their mechanism of action remain unknown. Our long-term goal is to understand the role of PON2 and PONS proteins in physiology and disease. During the last grant period, we have developed transgenic/knockout mouse models for PON2 and PONS genes, and provided the first in vivo evidence for the anti-atherogenic functions of PON2 and PONS proteins. We have also demonstrated that oxidized phospholipids or lipid peroxidation products are not direct substrates for purified PON enzymes, suggesting that direct inactivation of atherogenic oxidized phospholipids is not a key mechanism of action of PON proteins. We propose that the anti-atherogenic activities of PON proteins are a result of their activity towards a class of unidentified pro-inflammatory lipo-lactones that participate in LDL oxidation. Interestingly, in a very exciting turn of events, we recently discovered that PON2 and PONS proteins degrade gram-negative bacterial density-dependent sensing molecules termed acyl homoserine lactones (AHL) involved in gram-negative virulence. AHLs are lipo-lactones. Since gram-negative virulence is well established in the pathology of inflammatory diseases, including atherosclerosis, we propose that protection against pro-inflammatory pathways mediated by gram-negative virulence factors, such as AHLs, and other unidentified pro-inflammatory lipo-lactones, is a key physiological function of PON proteins. We will test this hypothesis in PON2 and PONS transgenic/knockout mouse models under two specific aims to 1) investigate the molecular mechanisms and function of PON2 and PONS in mitigating the development of atherosclerosis and 2) determine whether PON2 and PONS play a role in host defense against pro-inflammatory quorum sensing molecules and gram-negative bacterial infection. We hypothesize that PON2 and PONS are a novel class of lactonases that degrade i) atherogenic lipo-lactones associated with atherosclerosis, and ii) pro-inflammatory acyl homoserine lactones associated with gram-negative bacteria, thus preventing the pathogenesis of inflammatory diseases.

描述（由申请人提供）：副氧蛋白酶（PON）基因家族由三个家庭成员组成，分别是PON1，PON2和PON。 PON基因与包括动脉粥样硬化在内的几种炎症性疾病的发病机理有关。所有三种PON蛋白都具有抗氧化特性和乳糖酶活性。但是，PON蛋白的生理底物及其作用机理仍然未知。我们的长期目标是了解PON2和PON蛋白在生理和疾病中的作用。在最后一个赠款期间，我们开发了用于PON2和PON基因的转基因/基因敲除小鼠模型，并为PON2和PONS蛋白的抗动脉粥样硬化功能提供了第一个体内证据。我们还证明，氧化的磷脂或脂质过氧化产物不是纯化的PON酶的直接底物，这表明直接失活动脉粥样硬化氧化磷脂不是PON蛋白质作用的关键机制。我们建议PON蛋白的抗动脉粥样硬化活性是它们对参与LDL氧化的一类未鉴定的促炎性脂肪 - 内酯的活性。有趣的是，在一个非常令人兴奋的事件中，我们最近发现PON2和PON蛋白降解了革兰氏阴性酯（AHL）所涉及革兰氏阴性病毒力的革兰氏阴性密度依赖性传感分子（AHL）。 AHL是Lipo-Lactones。由于革兰氏阴性毒性在炎症性疾病的病理学中已经很好地确定，包括动脉粥样硬化，我们建议保护革兰氏阴性毒力因素（例如AHL和其他未鉴定的未识别的促炎性脂肪酮）对促炎性途径的保护，这是PON蛋白质的关键生理功能。我们将在PON2和PONS转基因/基因敲除小鼠模型中检验这一假设，以两个具体的目的为1）研究PON2和PON在减轻动脉粥样硬化的发展中的分子机制和功能，以及2）确定PON2和PONS在宿主防御中是否起作用，在宿主防御促进摄像症中是否起作用，以针对促触及的造成疫苗症状的传感分子和Gram-nectime contimial takection toctime toctimation。我们假设PON2和PON是一种新型的乳突酶，降解I）与动脉粥样硬化相关的动脉粥样硬化脂肪 - 乳乳糖酮，以及II）促炎性酰基均与革兰氏阴性细菌相关的促炎性酰基同素内酯，从而阻止了炎症性疾病的病原体。