Immune Reactants, Cholesterol and Atherosclerosis

免疫反应物、胆固醇和动脉粥样硬化

• 批准号: 6818563
• 负责人: ALLISON B REISS
• 金额: $ 22.79万
• 依托单位: NYU WINTHROP HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-01 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6818563
• 关键词: atherosclerosis; cholesterol; clinical research; enzyme activity; enzyme induction /repression; genetically modified animals; homeostasis; human subject; immune complex; immune response; immunoregulation; inflammation; laboratory mouse; longitudinal human study; macrophage; membrane transport proteins; mitogen activated protein kinase; molecular pathology; oxidoreductase inhibitor; oxygenases; protein localization; purinergic receptor; receptor expression; rheumatoid arthritis; steroid metabolism; systemic lupus erythematosus; tissue /cell culture

DESCRIPTION (provided by applicant): Recognition of the factors associated with maintaining cholesterol balance may illuminate the pathological mechanisms involved in diseases caused by cholesterol excess, with atherosclerosis the leading example. Homeostatic mechanisms that orchestrate cholesterol balance in the vessel wall and defend against atherosclerosis involve reverse cholesterol transport (RCT) from arterial wall to liver. A central mediator of RCT is the enzyme cholesterol 27-hydroxylase (27-OHase). 27-OHase both facilitates cholesterol transport to the liver and, by generating oxysterol signaling molecules, promotes expression of other RCT proteins, specifically ATP binding cassette transporter 1 (ABCA1). Inflammation is an integral feature of atherosclerosis. The autoimmune disorders systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) are characterized by high levels of circulating immune reactants and increased risk of atherosclerosis. We have shown that immune reactants affect cellular cholesterol flux by markedly decreasing 27-OHase and ABCA1 expression. We postulate that, in patients with autoimmune disorders, disruption of cholesterol homeostasis by immune reactants leads to accelerated atherosclerosis. To better understand the immunological mechanisms underlying development of atherosclerosis and to begin to counteract the atherogenic consequences, we propose 4 aims: 1) effect of over- and under- expression of 27-OHase on receptors and transport proteins involved in cholesterol flux, with the addition of a pathophysiologic correlate of atherogenesis: quantitation of foam cell transformation of THP-1 macrophages under the various conditions described; 2) immunomodulatory effects of serum from SLE and RA patients on these cholesterol transport/receptor proteins; 3) mechanisms of up regulation of 27-OHase via adenosine receptor agonists and consequent effects on cholesterol trafficking and 4) therapeutic intervention (statins, adenosine agonists) on cholesterol transport/receptor protein gene expression in a murine model (apolipoprotein E knockout mouse).

描述（由申请人提供）：识别与维持胆固醇平衡相关的因素可能会阐明由胆固醇过量导致疾病引起的疾病的病理机制，而动脉粥样硬化为主要例子。在容器壁上编排胆固醇并防御动脉粥样硬化的稳态机制涉及从动脉壁到肝脏的反向胆固醇运输（RCT）。 RCT的中心介质是胆固醇27-羟化酶（27-橙酶）。 27-霍斯酶都促进胆固醇转运到肝脏，并通​​过产生氧化酚信号分子促进其他RCT蛋白的表达，特别是ATP结合盒式转运蛋白1（ABCA1）。炎症是动脉粥样硬化的组成部分。自身免疫性疾病全身性红斑狼疮（SLE）和类风湿关节炎（RA）的特征是高水平的循环免疫反应物和动脉粥样硬化的风险增加。我们已经表明，免疫反应物通过显着降低27-鹰骨和ABCA1表达来影响细胞胆固醇通量。我们假设，在患有自身免疫性疾病的患者中，免疫反应剂会破坏胆固醇稳态会导致动脉粥样硬化加速。为了更好地理解动脉粥样硬化发展的潜在发展的免疫机制并开始抵消动脉粥样硬化后果，我们提出了4个目标：1）27-霍斯体过度和不足的影响对受体和胆固醇通量涉及的传输蛋白的过度表达和添加了病理生物学纠正量的杂种量的量化foam的量化剂量的量子化的量子量： 2）SLE和RA患者血清对这些胆固醇转运/受体蛋白的免疫调节作用； 3）通过腺苷受体激动剂对27-橙酶的提高机制，从而对胆固醇运输的影响以及4）治疗干预（汀类药物，腺苷激动剂）对胆固醇传输/受体蛋白基因在鼠模型（载脂蛋白E敲除小鼠）中的胆固醇传输/受体蛋白基因表达的影响。