Gene Regulation of Atherosclerosis in Diabetic Animals

糖尿病动物动脉粥样硬化的基因调控

• 批准号: 6654928
• 负责人: RENEE C LEBOEUF
• 金额: $ 33.43万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-02-01 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6654928
• 关键词: antioxidants; atherosclerosis; biological models; cardiovascular disorder prevention; collagenase; diabetes mellitus; diabetes mellitus genetics; diabetic angiopathy; diet therapy; drug screening /evaluation; enzyme activity; functional /structural genomics; gap junctions; gene expression; genetic strain; genetic susceptibility; hyperglycemia; laboratory mouse; membrane channels; metalloendopeptidases; microarray technology; nonhuman therapy evaluation; nutrition related tag; oxidative stress; protease inhibitor; protein structure function

DESCRIPTION (provided by applicant): Our long term goal is to identify molecular mechanisms for the onset of accelerated atherosclerosis in diabetes mellitus. This will be accomplished by studying animal models susceptible to both diabetes and atherosclerosis. During the previous grant period, we developed new mouse models, which show remarkable changes at the artery wall due to diabetes. BALB and BALB.LDLR-/- mice develop vascular lesions which are accelerted by hyperglycemia but are independent of changes in plasma lipids. In contrast, C57BL/6 and C57BL/6.LDLR-/- develop lesions which are not reflective of hyperglycemia. We use this genetic difference to test the hypothesis that hyperglycemia modulates the expression and/or function of specific genes causing diabetic macrovascular disease, in three aims: Aim 1: Identify major gene(s) determining the increased atherosclerosis in response to hyperglycemia. We use microarray technology coupled to mouse genetics for validation to identify such genes. Aim 2: Determine the role of specific candidate gene pathways in diabetic vascular disease. We study candidate proteins of perlecan, MMP-9 and MMP-13, and connexins 43 and 45 in our mouse system. Aim 3: Determine whether interventions aimed at reducing oxidative stress or protease activity can protect BALB from diabetic vascular disease. Anti-oxidant diets and diets containing synthetic protease ihibitors are used to test the general role of these pathways in diabetic vascular disease. Together, this information will provide potential gene targets for future prediction and treatment of diabetic macrovascular disease in humans

描述（由申请人提供）：我们的长期目标是确定糖尿病中动脉粥样硬化加速发作的分子机制。这将通过研究易患糖尿病和动脉粥样硬化的动物模型来实现。在上一次资助期间，我们开发了新的小鼠模型，该模型显示出糖尿病引起的动脉壁显着变化。 BALB 和 BALB.LDLR-/- 小鼠会出现血管病变，这种病变会因高血糖而加速，但与血浆脂质的变化无关。相反，C57BL/6和C57BL/6.LDLR-/-产生的病变并不反映高血糖。我们利用这种遗传差异来检验高血糖调节引起糖尿病大血管疾病的特定基因的表达和/或功能的假设，目的有以下三个： 目标 1：识别决定高血糖反应中动脉粥样硬化增加的主要基因。我们使用微阵列技术与小鼠遗传学相结合进行验证以识别此类基因。目标 2：确定特定候选基因通路在糖尿病血管疾病中的作用。我们在小鼠系统中研究基底膜聚糖、MMP-9 和 MMP-13 以及连接蛋白 43 和 45 的候选蛋白。目标 3：确定旨在减少氧化应激或蛋白酶活性的干预措施是否可以保护 BALB 免受糖尿病血管疾病的影响。抗氧化饮食和含有合成蛋白酶抑制剂的饮食用于测试这些途径在糖尿病血管疾病中的一般作用。总之，这些信息将为未来预测和治疗人类糖尿病大血管疾病提供潜在的基因靶点