Creating Glucose Responsive Cardiovascular Complications

产生葡萄糖反应性心血管并发症

• 批准号: 7151062
• 负责人: Ira J Goldberg
• 金额: $ 42.58万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-04 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7151062
• 关键词: aldehyde reductase; apoptosis; atherosclerosis; biotechnology; cardiac myocytes; cooperative study; diabetes mellitus; diabetic angiopathy; dietary lipid; disease /disorder model; enzyme activity; gene expression; genetic manipulation; genetically modified animals; human genetic material tag; hyperglycemia; laboratory mouse; medical complication; model design /development; myocardium disorder; nutrition related tag; pathologic process; streptozotocin; transfection

DESCRIPTION (provided by applicant): The PIs of this application have developed techniques for producing and studying atherosclerosis using funds from the first AMDCC program. Specifically, we have found that streptozotocin-treated mice develop increased atherosclerosis in the presence of a transgene for human aldose reductase (hAR). We have also noted that hearts from these mice have areas of cardiac apoptosis. In addition, we have developed novel methods to study atherosclerosis regression that can be applied to studies of lesions in control and diabetic mice. Aim 1 To create new mouse models of diabetic cardiovascular disease: We propose to create two new genetically altered mice. Aim 1a is to use the tet on system to allow expression of hAR in a time dependent manner. This system will allow us to test whether hAR expression in established lesions alters plaque morphology. These animals can also be used to produce tissue specific expression of hAR. Aim 1b is to produce mice with expression of hAR in cardiomyocytes. These mice, we hypothesize, will develop cardiomyopathy with diabetes. Aim 2 To study the development of vascular lesions in diabetic mice: Mild diabetes due to deficiency of Pdx1 or high fat diets did not alter atherosclerosis in Ldlr-/- mice. In addition, Pdx1 did not affect regression after transplant of arteries containing atherosclerosis. We will use two additional methods to generate hyperglycemia, Akita and high fat diets on the FVB background, in Ldlr-/- mice ¿ hAR. Increased vascular disease in STZ-treated hAR mice could result from greater monocyte/macrophage accumulation in lesions, or could be secondary to a defect in lesion regression. Both processes will be studied in vivo and mechanistic information obtained by studying gene and protein expression.

描述（由申请人提供）： 该申请的 PI 使用第一个 AMDCC 计划的资金开发了产生和研究动脉粥样硬化的技术。具体来说，我们发现，在存在人醛糖还原酶 (hAR) 转基因的情况下，经链脲佐菌素治疗的小鼠会出现动脉粥样硬化。还指出，这些小鼠的心脏具有心脏凋亡区域。此外，我们还开发了研究动脉粥样硬化消退的新方法，可应用于对照和糖尿病病变的研究。老鼠。 目标 1 创建糖尿病心血管疾病的新小鼠模型：我们建议创建两种新的基因改造小鼠。目标 1a 是使用 tet 系统以时间依赖性方式表达 hAR。该系统将允许我们测试是否。已建立的病变中的 hAR 表达也可用于产生 hAR 的组织特异性表达。我们追踪的这些小鼠将出现心肌病。患有糖尿病。 目标 2 研究糖尿病小鼠血管病变的发展：Pdx1 缺乏或高脂肪饮食导致的轻度糖尿病不会改变 Ldlr-/- 小鼠的动脉粥样硬化。此外，Pdx1 不会影响含有动脉粥样硬化的动脉移植后的消退。我们将使用另外两种方法在 Ldlr-/- 小鼠中在 FVB 背景下产生高血糖、秋田犬和高脂肪饮食 ¿ hAR。STZ 治疗的 hAR 小鼠中血管疾病的增加可能是由于病变中单核细胞/巨噬细胞的积累增多，或者可能是继发于病变消退的缺陷，这两个过程将在体内进行研究，并通过研究基因和蛋白质表达获得机制信息。 。