Cell Signaling: Macrovascular Complications of Diabetes

细胞信号转导：糖尿病的大血管并发症

• 批准号: 6683625
• 负责人: Karin E. Bornfeldt
• 金额: $ 30.32万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-30 至 2005-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6683625
• 关键词: atherosclerotic plaque; cell proliferation; cellular pathology; diabetic angiopathy; dietary lipid; growth factor receptors; hyperglycemia; insulinlike growth factor; laboratory mouse; linoleate; lipoprotein lipase; macrophage; mixed tissue /cell culture; nutrition related tag; oleate; platelet derived growth factor; protein kinase; radiotracer; swine; vascular smooth muscle

DESCRIPTION (provided by applicant): A majority of people with diabetes die of cardiovascular disease caused by atherosclerosis that is accelerated by diabetes. The factors that drive diabetes-accelerated atherosclerosis are still poorly understood. Our recent studies on a new porcine model show that diabetes in combination with elevated lipid intake causes increased accumulation and proliferation of arterial smooth muscle cells (SMCs) in lesions of atherosclerosis. The increased SMC proliferation occurs concomitant with hyperglycemia and elevated levels of plasma triglycerides. High glucose levels are not sufficient to induce SMC proliferation, but certain fatty acids common in triglycerides (oleate and linoleate) stimulate SMC proliferation in the presence of insulin-like growth factor I (IGF-I). We propose that diabetes leads to an increased amount of IGF-I and of lipoprotein lipase in lesion macrophages, and that lipoprotein lipase degrades triglycerides into free fatty acids that act in synergy with IGF-I to stimulate SMC proliferation. Our goal for the next five years is to address the following questions: 1. Do oleate and linoleate enhance the growth-promoting effects of IGF-I on SMCs? 2. How do oleate and linoleate synergize with the growth-promoting action of IGF-I in SMCs? 3. Does lipoprotein lipase produced by lipid loaded macrophages increase SMC proliferation by generating oleate and linoleate? 4. Does glucose or lipids associated with diabetes stimulate SMC proliferation, lipoprotein lipase and IGF-I in lesions of atherosclerosis and does lack of macrophage-derived lipoprotein lipase result in reduced SMC proliferation? We will use several animal models of diabetes-associated atherosclerosis, isolated arterial SMCs for signal transduction studies as well as a co-culture model of monocyte derived macrophages and SMCs. Increased understanding of the regulation of SMC proliferation and accumulation in diabetic lesions of atherosclerosis may provide the basis information necessary for development of highly specific drugs that can prevent lesion progression and formation of vulnerable lesions that are likely to cause the clinical symptoms of cardiovascular complications in diabetes.

描述(申请人提供)：大多数糖尿病患者死于 动脉粥样硬化引起的心血管疾病 糖尿病。驱动糖尿病加速的动脉粥样硬化的因素仍然是 人们对此知之甚少。我们最近对一种新的猪模型的研究表明，糖尿病 再加上脂肪摄入量增加会导致蓄积增加和 血管内皮细胞增殖的实验研究 动脉硬化。SMC增殖增加伴随着 高血糖和血浆甘油三酯水平升高。高血糖水平 不足以诱导SMC增殖，但某些脂肪酸常见 在甘油三酯(油酸盐和亚油酸盐)中刺激SMC增殖 存在胰岛素样生长因子I(IGF-I)。我们建议糖尿病患者 导致皮损中IGF-I和脂蛋白脂肪酶的含量增加 巨噬细胞，脂蛋白脂肪酶将甘油三酯降解为游离脂肪 与IGF-I协同作用以刺激SMC增殖的酸。我们的目标 今后五年要解决以下问题：1.做油酸和 亚油酸增强IGF-I对SMC的促生长作用？2.如何 油酸和亚油酸盐与IGF-I促生长作用的协同作用 SMC？3.脂质负载的巨噬细胞产生的脂蛋白脂酶增加吗？ SMC通过产生油酸和亚油酸而增殖？4.葡萄糖或脂类 与糖尿病相关的刺激SMC增殖、脂蛋白脂酶和 IGF-I在动脉粥样硬化病变中的作用及巨噬细胞来源的缺失 脂蛋白脂酶导致SMC增殖减少？我们将使用几个 糖尿病相关动脉粥样硬化的动物模型，分离的动脉SMC 用于信号转导研究以及单核细胞共培养模型 衍生的巨噬细胞和SMC。增加对SMC监管的理解 糖尿病动脉粥样硬化病变中的增殖和积聚可能 提供开发高度专门性的基础信息 可防止病变进展和易损病变形成的药物 很可能会导致心血管并发症的临床症状 糖尿病患者。