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

基本信息

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
项目类别：
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

项目摘要

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，与心血管疾病的风险增加有关。有证据表明炎性蛋白血清淀粉样蛋白A（SAA）在动脉粥样硬化的发病机理。 SAA具有可能涉及的几种生物学功能在动脉粥样硬化中，包括其结合能力和由血管蛋白聚糖保留并募集的能力炎性细胞，例如单核细胞。研究概述了研究升高的作用糖尿病大血管疾病发病机理中的SAA水平，并评估潜力 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Apo B的脂蛋白和HDL中的动脉粥样硬化潜力和2型和类型的小鼠模型中的HDL 1型糖尿病，以确定SAA1和SAA2缺陷是否是主要诱导循环形式 SAA，影响血浆脂蛋白组成和功能，以及小鼠胰岛素模型中的动脉粥样硬化耐药性和2型糖尿病，并研究诱导SAA同工型的局部过表达的作用在LDLR - / - 小鼠喂养糖尿病饮食中的动脉粥样硬化的巨噬细胞中。将使用的方法将包括体外研究，以确定潜在的机制，从而使糖尿病诱导的SAA增加水平会影响动脉粥样硬化发病机理涉及的生物学过程。我们也会使用分子方法抑制响应糖尿病饮食的SAA升高。这会允许我们评估主要诱导形式的SAA促进动脉粥样硬化的作用。最后，我们会的使用新型逆转录病毒载体在巨噬细胞中有选择地表达各种SAA同工型动脉壁的巨噬细胞。这种方法将使我们能够确定当地的过表达是否巨噬细胞的SAA同工型增加了动脉粥样硬化。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涉及1型和2型糖尿病中的SAA。