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)： 这个应用程序的PI已经开发了使用第一个AMDCC计划的资金来生产和研究动脉粥样硬化的技术。具体地说，我们发现链脲佐菌素处理的小鼠在人类醛糖还原酶(HAR)转基因存在的情况下发展为动脉粥样硬化加重。我们还注意到，这些小鼠的心脏有心肌细胞凋亡的区域。此外，我们开发了新的方法来研究动脉粥样硬化的消退，可以应用于对照组和糖尿病小鼠的病变研究。 目的1建立新的糖尿病心血管疾病小鼠模型：我们建议建立两个新的基因改变的小鼠。目标1a是使用tet on系统以时间依赖的方式允许HAR的表达。该系统将使我们能够测试HAR在已建立的病变中的表达是否改变斑块的形态。这些动物也可以用来产生组织特异性表达的HAR。目的1b建立心肌细胞表达HAR的小鼠。我们推测，这些小鼠会患上糖尿病心肌病。 目的2研究糖尿病小鼠血管病变的发生发展：PDX1缺乏或高脂饮食导致的轻度糖尿病并不改变LDLR-/-小鼠的动脉粥样硬化。此外，Pdx1不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来产生高血糖，秋田和高脂肪饮食在FVB背景下，在Ldlr-/-小鼠？Har中。STZ治疗的HAR小鼠血管疾病的增加可能是由于病变中更多的单核/巨噬细胞聚集所致，也可能是继发于病变消退中的缺陷。这两个过程都将在体内进行研究，并通过研究基因和蛋白质的表达获得机制信息。