Modeling Diabetic Cardiomyopathy and Microangiopathy

糖尿病心肌病和微血管病建模

• 批准号: 7151864
• 负责人: E Dale Abel
• 金额: $ 37.38万
• 依托单位: UNIVERSITY OF UTAH
• 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/7151864
• 关键词: angiogenesis; angiogenesis factor; biotechnology; cardiovascular function; cooperative study; diabetic angiopathy; diabetic cardiomyopathy; disease /disorder model; fatty acids; genetic manipulation; genetically modified animals; insulin dependent diabetes mellitus; insulin receptor; ischemia; laboratory mouse; ligase; medical complication; mitochondria; model design /development; noninsulin dependent diabetes mellitus; pathologic process; superoxides; transfection; ventricular hypertrophy

DESCRIPTION (provided by applicant): This proposal is submitted to become a pathobiology site in the renewal of the Animal Models of Diabetic Complications Consortium (AMDCC). The University of Utah site proposes to generate two mouse models. The first will address mechanisms that are responsible for diabetic cardiomyopathy, and the second will model the role of impaired angiogenesis and arteriogenesis in the pathogenesis of ischemic complications of diabetes. Our studies in the first phase of the consortium revealed that diabetic cardiomyopathy (particularly in type 2 diabetes) was characterized by impaired myocardial insulin action, mitochondria! dysfunction, oxidative stress, increased FA utilization, decreased glucose utilization and lipotoxicity. Mice with cardiomyocyte-restricted deletion of insulin receptors (CIRKO), developed many of the features of diabetic cardiomyopathy but did not have a persistent increase in FA oxidation, did not develop lipotoxicity and had modest defects in cardiac function. We therefore propose to introduce into CIRKO mice an Acyl-CoA synthetase transgene that will modestly increased myocardial FA delivery in a sensitized background of mitochondrial superoxide (Sod2) haploinsufficency. We will then determine if these mice meet established AMDCC criteria for diabetic cardiomyopathy, determine if they exhibit characteristic defects in mitochondrial function and substrate utilization and test the hypothesis that they will be more susceptible to dysfunction in the face of LV hypertrophy.This model represents a powerful platform with which to test the direct effect of various therapeutic strategies on diabetic cardiomyopathy, independently of effects on systemic metabolism. We will also generate a mouse in the type -1 diabetes (Akita) background with temporal and cell-type restricted expression of a novel angiogenic factor netrin 1. We will use this mouse to determine if the maintenance of arteriogenesis and angiogenesis, by activating this transgene in the heart or the hind-limb will be sufficient to ameliorate the accelerated LV remodeling that characterizes diabetic hearts following coronary artery ligation, or reverse impaired recovery of hind-limb perfusion that occurs in diabetic animals following femoral artery occlusion. This model will also be a powerful platform with which to evaluate the role of impaired angiogenesis (in the pathogenesis), or therapeutic angiogenesis (in the treatment) of other ischemic complications of diabetes such as impaired wound healing, neuropathy or nephropathy.

描述（由申请人提供）： 该建议被提交为糖尿病并发症联盟动物模型（AMDCC）的续签中的病原体学位。犹他大学网站建议生成两种鼠标模型。第一个将解决负责糖尿病心肌病的机制，第二个将模拟受损的血管生成和动脉生成在糖尿病缺血并发症的发病机理中的作用。我们在财团的第一阶段的研究表明，糖尿病性心肌病（尤其是在2型糖尿病中）的特征是心肌胰岛素作用受损线粒体！功能障碍，氧化应激，FA利用率增加，葡萄糖利用率降低和脂毒性。具有胰岛素受体（CIRKO）的心肌细胞限制缺失的小鼠发展出许多糖尿病心肌病的特征，但没有持续增加FA氧化，并没有发展出脂肪毒性，并且具有适度的缺陷。因此，我们建议将Cirko小鼠引入酰基-COA合成酶转基因，该酰基合成酶转基因将在线粒体超氧化物（SOD2）单倍耐酸的敏感背景下适度增加心肌FA的递送。然后，我们将确定这些小鼠是否符合糖尿病心肌病的既定AMDCC标准，确定它们是否在线粒体功能和利用线粒体功能和底物利用中表现出特征性缺陷独立于对系统性代谢的影响。 We will also generate a mouse in the type -1 diabetes (Akita) background with temporal and cell-type restricted expression of a novel angiogenic factor netrin 1. We will use this mouse to determine if the maintenance of arteriogenesis and angiogenesis, by activating this transgene in the heart or the hind-limb will be sufficient to ameliorate the accelerated LV remodeling that characterizes diabetic hearts following冠状动脉连接，或股动脉闭塞后糖尿病动物中发生的后脂灌注的恢复。该模型还将是一个强大的平台，可以通过它评估受损（在发病机理）或治疗性血管生成（在治疗中）的作用（在治疗中）的其他缺血性并发症，例如伤口愈合受损，神经病或肾病。