Role of Serum Amyloid A in Diabetic Vascular Disease

血清淀粉样蛋白 A 在糖尿病血管疾病中的作用

• 批准号: 7548830
• 负责人: ALAN CHAIT
• 金额: $ 46.01万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7548830
• 关键词: A Mouse; Affect; Apolipoproteins B; Arterial Fatty Streak; Arteries; Atherosclerosis; Binding; Biological Process; Blood Vessels; Cell Adhesion Molecules; Cells; Characteristics; Cholesterol; Cholesterol Homeostasis; Chronic; Consumption; Diabetes Mellitus; Diabetic Angiopathies; Diabetic mouse; Diet; Elevation; Endothelial Cells; Fatty Liver; High Density Lipoproteins; Human; Hyperglycemia; In Vitro; Inflammation; Inflammatory; Insulin Resistance; Insulin-Dependent Diabetes Mellitus; Knockout Mice; Link; Lipoproteins; Liver; Low Density Lipoprotein Receptor; Measures; Metabolic syndrome; Molecular; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Obese Mice; Obesity; Pathogenesis; Pathway interactions; Plasma; Play; Population; Principal Investigator; Process; Production; Property; Protein Isoforms; Protein Overexpression; Proteins; Proteoglycan; Proteome; Proteomics; Range; Recruitment Activity; Retroviral Vector; Risk Factors; Role; Serum amyloid A protein; Shotguns; Testing; Transplantation; Vascular Diseases; atherogenesis; cardiovascular disorder risk; diabetic; dyslipoproteinemia; feeding; insight; lipid metabolism; macrophage; macrovascular disease; monocyte; mouse model; non-diabetic; novel; particle; programs; protein transport; response; reverse cholesterol transport; type I and type II diabetes

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.

糖尿病是一种慢性炎症状态，与心血管疾病风险增加相关。 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 具有多种可能涉及的生物学功能 在动脉粥样硬化形成中，包括其结合血管蛋白聚糖并被血管蛋白聚糖保留以及募集的能力 炎症细胞，例如单核细胞。概述的研究旨在调查升高的作用 SAA 水平在糖尿病大血管疾病发病机制中的作用，并评估其潜力 SAA 影响动脉粥样硬化过程的机制。为此，我们建议确定 2 型和 2 型小鼠模型中含载脂蛋白 B 的脂蛋白和 HDL 中 SAA 的致动脉粥样硬化潜力 1 型糖尿病，以确定 SAA1 和 SAA2（主要诱导循环形式）是否存在缺陷 SAA，影响胰岛素小鼠模型中的血浆脂蛋白组成和功能以及动脉粥样硬化 耐药性和 2 型糖尿病，并研究诱导型 SAA 亚型局部过度表达的作用 巨噬细胞对喂食致糖尿病饮食的 LDLR-/- 小鼠动脉粥样硬化的影响。将使用的方法将 包括体外研究以确定糖尿病引起的 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。我们也将使用 抑制因糖尿病饮食而发生的 SAA 升高的分子方法。这将 让我们能够评估 SAA 主要诱导形式在促进动脉粥样硬化形成中的作用。最后，我们将 使用新型逆转录病毒载体选择性过表达巨噬细胞中的各种 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局部过度表达是否 巨噬细胞对 SAA 亚型的分解会增加动脉粥样硬化。总的来说，这些研究将使我们能够 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 型和 2 型糖尿病均涉及 SAA。