Role of Serum Amyloid A in Diabetic Vascular Disease

糖尿病是一种慢性炎症状态，与心血管疾病风险增加有关。 越来越多的证据表明，炎症蛋白，血清淀粉样蛋白A（SAA），在 动脉粥样硬化的发病机制。SAA具有多种生物学功能， 在动脉粥样硬化形成中，包括其结合和被血管蛋白聚糖保留的能力， 炎症细胞如单核细胞。概述的研究建议调查升高的 SAA水平在糖尿病大血管病变发病机制中的作用，并评估其潜在的 SAA影响动脉粥样硬化过程的机制。为此，我们建议确定 SAA在含载脂蛋白B的脂蛋白和HDL中的致动脉粥样硬化潜力在2型和 1型糖尿病，以确定是否缺乏SAA 1和SAA 2，主要的诱导循环形式， SAA，影响血浆脂蛋白组成和功能，并在小鼠动脉粥样硬化模型的胰岛素 抵抗和2型糖尿病，并研究诱导SAA亚型的局部过表达的作用， 巨噬细胞对LDLR-/-小鼠动脉粥样硬化形成的影响。将采用的方法将 包括体外研究以确定糖尿病诱导SAA增加的潜在机制 水平影响动脉粥样硬化发病机制中涉及的生物过程。我们还将使用 分子方法来抑制响应于致糖尿病饮食而发生的SAA升高。这将 使我们能够评估SAA的主要诱导形式促进动脉粥样硬化形成的作用。最后我们将 使用一种新的逆转录病毒载体在巨噬细胞中选择性过表达各种SAA亚型，包括 动脉壁的巨噬细胞。这种方法将使我们能够确定是否局部过度表达 SAA同种型增加动脉粥样硬化。总的来说，这些研究将使我们 评估通过炎症途径将糖尿病和动脉粥样硬化联系起来的潜在机制， 1型糖尿病和2型糖尿病患者的SAA。

Diabetes is a chronic inflammatory state that is associated with an increased risk of cardiovascular disease. Evidence is accumulating that the inflammatory protein, serum amyloid A (SAA), plays an important role in the pathogenesis of atherosclerosis. SAA has several biological functions that could potentially be involved in atherogenesis, including its ability to bind and be retained by vascular proteoglycans and to recruit inflammatory cells such as monocytes. The studies outlined propose to investigate the role of elevated levels of SAA in the pathogenesis of macrovascular disease in diabetes, and to evaluate potential mechanisms by which SAA affects the atherogenic process. To that end we propose to determine the atherogenic potential of SAA in apo B-containing lipoproteins and HDL in mouse models of both type 2 and type 1 diabetes, to establish whether deficiencies of SAA1 and SAA2, the major inducible circulating forms of SAA, affect plasma lipoprotein composition and function, and atherosclerosis in a mouse model of insulin resistance and type 2 diabetes, and to investigate the role of local over-expression of inducible SAA isoforms in macrophages on atherogenesis in LDLR-/- mice fed a diabetogenic diet. Approaches that will be used will include in vitro studies to determine potential mechanisms whereby diabetes-induced increases in SAA levels affect biological processes involved in the pathogenesis of atherosclerosis. We also will use molecular approaches to inhibit the elevation of SAA that occurs in response to a diabetogenic diet. This will allow us to evaluate the role of the major inducible forms of SAA to facilitate atherogenesis. Finally, we will use a novel retroviral vector to selectively overexpress the various SAA isoforms in macrophages, including macrophages of the artery wall. This approach will allow us to determine whether the local overexpression of SAA isoforms by macrophages increases atherosclerosis. Collectively these studies will allow us to evaluate potential mechanisms that links diabetes and atherosclerosis via an inflammatory pathway that involves SAA in both type 1 and type 2 diabetes.