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Pro-inflammatory S100A12 in atherosclerosis and acute coronary syndrome

动脉粥样硬化和急性冠状动脉综合征中的促炎性 S100A12

基本信息

批准号：
7680267
负责人：
Marion A Hofmann Bowman
金额：
$ 12.42万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-30 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7680267
关键词：
Abbreviations Age Anti-Inflammatory Agents Anti-inflammatory Apolipoprotein E Area Arterial Fatty Streak Arterial Injury Atherosclerosis Backcrossings Binding Binding Proteins Birth Blood Platelets Blood Vessels Breeding Cell Culture Techniques Cell Proliferation Cell Surface Receptors Cells Cellular Stress Cessation of life Chronic Coronary Cromoglicic Acid Development Diabetes Mellitus Disease Endothelial Cells Functional disorder Future Gene Expression Generations HMGB1 Protein Harvest Human ITGAM gene In Vitro Inflammation Inflammation Mediators Inflammatory Injury Knockout Mice LDL-Receptor Related Protein 1 Lesion Light Link Matrix Metalloproteinases Mediating Modeling Mucocutaneous Lymph Node Syndrome Mus Pathogenesis Pathway interactions Patients Personal Communication Pharmaceutical Preparations Proteins Research Personnel Role S100 Proteins S100A12 gene Serum Signal Transduction Smooth Muscle Smooth Muscle Myocytes Testing Tetracycline Control Tetracyclines Time Tissues Trans-Activators Transgenes Transgenic Mice Umbilical vein Universities Vasculitis acute coronary syndrome cellular targeting cytokine diabetic patient femoral artery interest macrophage mast cell migration mouse model novel percutaneous coronary intervention promoter protein B receptor receptor for advanced glycation endproducts research study response vascular inflammation

项目摘要

DESCRIPTION (provided by applicant): I am interested in mechanisms of vascular disturbances related to atherosclerosis, specifically in the contribution of the pro-inflammatory S100/ calgranulins proteins. S100 A12 was identified in human atheromatous vasculature as well as in the coronary plaque of diabetic patients with sudden coronary death suggesting a role in atherosclerosis and plaque destabilization. Increased serum S100A12 concentrations are present in patients with chronic inflammatory diseases including patients with vasculitis such as Kawasaki disease and in diabetic patients. One mechanism by which S100A12 promotes inflammation is by activation of the receptor for Advanced Glycation Endproducts (RAGE), a receptor strongly linked to vascular dysfunction and atherosclerosis. Specifically, I previously showed that RAGE is a central cell surface receptor for S100A12 leading to activation of endothelial cells and macrophages, cells critically involved in sustained inflammation and vascular dysfunction. I propose to test the hypothesis that S100A12 accelerates atherosclerosis by generating two transgenic mouse models with S100A12 expression targeted to the smooth muscle cells by using the SM22-a promoter and targeted to macrophages by using the CD11b promoter. Two models of vascular dysfunction will be studied: First, I will examine vascular response to a model of arterial injury as there is evidence that S100A12 modulates smooth muscle cell proliferation and migration. Second, I will bred the S100A12 transgenic mice with atherosclerosis prone ApoE null mice and assess at various time points. I expect that S100A12 will accelerate the development of atherosclerosis and I will examine if S100A12 mediates these effects in a RAGE-dependent and in RAGEindependent manner. To test this hypothesis, the S100A12 mice will be bred with the RAGE null and RAGE/ApoE double null mice. These experiments will shed light into the mechanism of pro-inflammatory and pro-thrombotic actions of S100A12 and will provide information on whether these proteins may serve as an important cellular target for the development of new drugs to treat atherosclerosis.

描述（由申请人提供）：我对与动脉粥样硬化相关的血管紊乱机制感兴趣，特别是促炎性 S100/钙颗粒蛋白的作用。 S100 A12 在人类动脉粥样化脉管系统以及患有冠心病猝死的糖尿病患者的冠状动脉斑块中被鉴定出，表明其在动脉粥样硬化和斑块不稳定中发挥作用。慢性炎症性疾病患者（包括川崎病等血管炎患者）和糖尿病患者的血清 S100A12 浓度升高。 S100A12 促进炎症的一种机制是激活晚期糖基化终产物 (RAGE) 受体，该受体与血管功能障碍和动脉粥样硬化密切相关。具体来说，我之前表明，RAGE 是 S100A12 的中央细胞表面受体，可导致内皮细胞和巨噬细胞的激活，这些细胞与持续炎症和血管功能障碍密切相关。我建议通过生成两种转基因小鼠模型来检验 S100A12 加速动脉粥样硬化的假设，其中 S100A12 表达通过使用 SM22-a 启动子靶向平滑肌细胞，并通过使用 CD11b 启动子靶向巨噬细胞。将研究两种血管功能障碍模型：首先，我将检查血管对动脉损伤模型的反应，因为有证据表明 S100A12 调节平滑肌细胞增殖和迁移。其次，我将用易患动脉粥样硬化的 ApoE 缺失小鼠培育 S100A12 转基因小鼠，并在不同时间点进行评估。我预计 S100A12 将加速动脉粥样硬化的发展，我将检查 S100A12 是否以 RAGE 依赖和 RAGE 独立的方式介导这些效应。为了检验这一假设，将 S100A12 小鼠与 RAGE null 小鼠和 RAGE/ApoE 双 null 小鼠交配。这些实验将揭示 S100A12 的促炎和促血栓形成作用机制，并将提供有关这些蛋白质是否可以作为开发治疗动脉粥样硬化新药的重要细胞靶标的信息。