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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：
7530538
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/7530538
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 Proliferation Cell Surface Receptors Cells Cessation of life Chronic Coronary Cromoglicic Acid Cultured Cells Daily Development Diabetes Mellitus Disease Endothelial Cells Functional disorder Future Gene Expression Generations HMGB1 Protein Harvest Human ITGAM gene In Vitro Inflammation Inflammatory Injury Intervention Knockout Mice LDL-Receptor Related Protein 1 Lesion Light Link Matrix Metalloproteinases Mediating Mediator of activation protein 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 Stress Testing Tetracycline Tetracycline Control Tetracyclines Time Tissues Trans-Activators Transgenes Transgenic Mice Transgenic Organisms Umbilical vein Universities Vasculitis Week acute coronary syndrome cellular targeting concept cytokine diabetic femoral artery human S100A12 protein interest macrophage mast cell migration mouse model novel promoter protein B receptor receptor for advanced glycation endproducts research study response size 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在人类动脉粥样硬化血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，表明在动脉粥样硬化和斑块不稳定中起作用。血清S100 A12浓度升高存在于慢性炎性疾病患者中，包括血管炎患者如川崎和糖尿病患者。S100 A12促进炎症的一种机制是通过激活晚期糖基化终产物（Advanced Glycation Endproducts，简称AGEs）受体，这是一种与血管功能障碍和动脉粥样硬化密切相关的受体。具体来说，我以前表明，S100 A12是一种中央细胞表面受体，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。我建议通过建立两个转基因小鼠模型来验证S100 A12加速动脉粥样硬化的假设，其中S100 A12表达通过使用SM 22-a启动子靶向平滑肌细胞和通过使用CD 11b启动子靶向巨噬细胞。将研究血管功能障碍的两种模型：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S100 A12调节平滑肌细胞增殖和迁移。第二，将S100 A12转基因小鼠与动脉粥样硬化易感性ApoE基因敲除小鼠共育，并在不同时间点进行评估。我预计S100 A12将加速动脉粥样硬化的发展，我将检查S100 A12是否以RAGE依赖和RAGE独立的方式介导这些作用。为了检验这一假设，S100 A12小鼠将与ApoE无效和ApoE/ApoE双无效小鼠交配。这些实验将揭示S100 A12的促炎和促血栓形成作用的机制，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点的信息。