REDUCING DIABETIC CARDIOMYOPATHY: INCREASING GLYCOLYSIS

申请人摘要 众所周知，糖尿病会减少心脏糖酵解。 此外，它 已知糖酵解受损易导致缺血性损伤， 心肌病和收缩缺陷。 这些心脏问题中的每一个 糖尿病性心肌病的特征 总之，这些发现表明 糖酵解减少在糖尿病性心肌病中有重要作用。 然而，糖尿病是一种复杂的疾病，心脏有许多缺陷， 在整个身体。 这一建议的重点是假设，有一个 糖酵解减少与糖尿病性心肌病之间的因果关系。 为了测试这一提议，申请人将生产四种不同的转基因植物， 表达基因以增加糖酵解的模型，特别是在心脏中。 GLUT 4葡萄糖转运蛋白，酵母己糖激酶， 二磷酸酶缺陷型2，6-磷酸果糖激酶/果糖-2，6-二磷酸酶 并且甘油醛3-磷酸脱氢酶将过表达。 中的每 这些基因控制糖尿病心脏中减少的活动， 控制有氧或缺血条件下的糖酵解。 申请人已经 已经开发了酵母己糖激酶模型，并证明增加 心脏糖酵解 糖酵解增加的转基因小鼠将被杂交 严重、长期和早发性糖尿病的转基因模型， 他们发现，糖尿病患者的形态和功能特征 心肌病 携带糖酵解转基因的糖尿病小鼠将 与无糖酵解的糖尿病小鼠相比， 转基因 将分析心脏的形态差异， 收缩性、对缺血的敏感性和线粒体损伤。 这些 研究将提供一个明确的测试糖酵解受损的作用， 糖尿病性心肌病和对缺血的敏感性。

Applicant's Abstract It is well established that diabetes reduces cardiac glycolysis. Further, it is known that impaired glycolysis predisposes to ischemic damage, cardiomyopathy and contractile deficits. Each of these cardiac problems is characteristic of diabetic cardiomyopathy. Together, these findings suggest that decreased glycolysis has an important role in diabetic cardiomyopathy. However, diabetes is a complex disease with many deficits in the heart and throughout the body. This proposal focuses on the hypothesis that there is a causal relationship between decreased glycolysis and diabetic cardiomyopathy. To test this proposal, the applicants will produce four separate transgenic models that express genes to increase glycolysis, specifically in the heart. Transgenes for the GLUT 4 glucose transporter, yeast hexokinase, bisphosphatase deficient 2,6 phosphofructo-kinase/fructose-2,6 bisphosphatase and glyceraldehyde 3-phosphate dehydrogenase will be overexpressed. Each of these genes controls an activity that is reduced in the diabetic heart and controls glycolysis under aerobic or ischemic conditions. The applicants have already developed the yeast hexokinase model and demonstrated increased cardiac glycolysis. Transgenic mice with increased glycolysis will be crossed to a transgenic model of severe, prolonged and early onset diabetes, which they have found to display morphological and functional features of diabetic cardiomyopathy. Diabetic mice carrying the glycolytic transgenes will be compared for signs of cardiomyopathy to diabetic mice without glycolytic transgenes. Hearts will be analyzed for differences in morphology, contractility, sensitivity to ischemia and mitochondrial damage. These studies will provide a definitive test of the role of impaired glycolysis in diabetic cardiomyopathy and sensitization to ischemia.