The Acute Phase Response in Atherosclerosis

描述（由申请人提供）：越来越多的证据支持炎症在动脉粥样硬化发展中的重要作用。动脉粥样硬化病变的演变部分是由炎症介质的作用引导的，在表面健康的受试者中，全身炎症标志物的存在与随后心血管疾病的发生呈正相关。然而，全身性炎症对动脉粥样硬化发展的作用尚不清楚。全身性炎症的主要组成部分，急性期反应（APR），是由两个阶段触发的。第一阶段导致损伤部位产生促炎细胞因子，如il - 1 β、肿瘤坏死因子α (TNFalpha)和IL-6。第二阶段涉及这些细胞因子对靶器官（如肝脏）的作用，在那里刺激或抑制急性期蛋白质的合成。IL-6是未来心肌梗死风险增加的一个指标，主要通过转录因子Stat3对APR基因发挥作用。Stat3以两种具有不同生化特性的异构体表达。使用替代剪接受体位点指定Stat3beta （Stat 3beta）异构体。我们使用了一种新的方法来产生选择性地不能合成stat3 β亚型的小鼠。我们的初步观察揭示了stat3 β在stat3介导的转录调节中的作用，并表明stat3 β对于全身炎症的正常恢复至关重要。为了探索Stat3亚型在急性期反应调控中的作用，以及急性期反应与动脉粥样硬化的关系，我们将追求三个目标。我们将通过全基因组微阵列分析，开发正常小鼠和stat3b缺陷小鼠肝脏和内皮细胞急性期反应的详细转录图谱。结合生化和计算方法，我们将定义stat3 β如何调节stat3应答基因的表达。第三，我们将通过在小鼠模型中检测stat3β缺乏对动脉粥样硬化发展的影响来验证慢性全系统炎症促进动脉粥样硬化发展的假设。

DESCRIPTION (provided by applicant): A growing body of evidence supports a prominent role for inflammation in the development of atherosclerosis. The evolution of atheromatous lesions is guided in part by the action of inflammatory mediators, and in apparently healthy subjects, the presence of systemic inflammatory markers is positively correlated with the subsequent occurrence of cardiovascular disease. Nonetheless, the contributions of systemic inflammation to development of atherosclerosis are not well understood. The major component of systemic inflammation, the acute phase response (APR), is triggered in two phases. The first phase leads to the production of proinflammatory cytokines such as IL-lbeta, tumor necrosis factor alpha (TNFalpha) and IL-6 at the site of injury. The second phase involves the action of those cytokines on target organs such as the liver, where synthesis of acute phase proteins is stimulated or suppressed. IL-6, an indicator of increased risk for future myocardial infarction, exerts its effects on APR genes principally through the transcription factor Stat3. Stat3 is expressed as two isoforms with distinct biochemical properties. The use of an alternative splice acceptor site specifies the Stat3beta (Stat 3beta) isoform. We have used a novel approach to generate mice that are selectively unable to synthesize the Stat3beta isoform. Our preliminary observations uncover a role for Stat3beta in the modulation of Stat3-mediated transcription, and suggest that Stat3beta is essential for normal recovery from systemic inflammation. To explore the role of Stat3 isoforms in the regulation of the acute phase response, and the relation of the acute phase response to atherosclerosis, we will pursue three aims. We will develop detailed transcriptional maps of the hepatic and endothelial acute phase responses in normal and Stat3b-deficient mice by genome-wide microarray assays. Using a combination of biochemical and computational approaches, we will define how Stat3beta modulates expression of Stat3-responsive genes. Third, we will test the hypothesis that chronic systemic inflammation promotes development of atherosclerosis by examining the influence of Stat3beta-deficiency on development of atherosclerosis in mouse models.