Gene Regulation of Atherosclerosis in Diabetic Animals

描述(由申请人提供)：我们的长期目标是确定糖尿病加速动脉粥样硬化发病的分子机制。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。在之前的资助期间，我们开发了新的小鼠模型，由于糖尿病，这些模型的动脉壁出现了显著的变化。BALB和BALB.LDLR-/-小鼠出现血管损伤，高血糖会加速这种损伤，但不受血脂变化的影响。相比之下，C57BL/6和C57BL/6.LDLR-/-出现的病变不能反映高血糖。我们利用这种遗传差异来验证高血糖调节导致糖尿病大血管病变的特定基因的表达和/或功能的假说，目的1：确定决定高血糖导致动脉粥样硬化增加的主要基因(S)。我们使用微阵列技术与小鼠遗传学相结合进行验证，以识别这些基因。目的2：确定特定候选基因通路在糖尿病血管病变中的作用。我们在我们的小鼠系统中研究了Perlecan，MMP9和MMP13，以及连接蛋白43和45的候选蛋白。目的3：确定旨在降低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被用来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。

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