Dysregulated fat utilization in diabetic cardiomyopathy

描述：（申请人？心功能不全发生在较高的 糖尿病患者的发病率，即使有危险因素，如冠状动脉 动脉疾病都有该提案旨在测试 心肌脂肪酸摄取和氧化速率过快假说 导致与糖尿病性心肌病相似病理性重构。到 为此，我们将重点放在过氧化物酶体增殖物激活受体a上， （PPARa），一种激活心脏脂肪的核受体转录因子 酸（FA）利用途径。转基因小鼠过表达PPARa， 心脏特异性方式（MHC-PPARa小鼠）的小鼠模型。因为PPARa 在调节编码细胞因子的基因的表达中起着关键作用。 FA利用酶，预测FA输入和氧化速率 在MHC-PPARa小鼠的心脏中将增加，这反过来可能导致 心脏肥大功能障碍最终衰竭的具体目标 该建议是1）表征MHC-PPARa小鼠的代谢表型。 2)表征MHC-PPARa小鼠的心脏结构和功能。3)到 将MHC-PPARa小鼠的心肌表型与 链脲佐菌素诱导的糖尿病心肌病模型，并确定 底物利用的改变在心肌梗死的发生和严重程度中的作用 功能障碍

DESCRIPTION: (Applicant?s abstract): Cardiac dysfunction occurs at a higher rate in patients with diabetes mellitus, even when risk factors, like coronary artery disease, are accounted for. This proposal is designed to test the hypothesis that excessive rates of myocardial fatty acid uptake and oxidation lead to pathologic remodeling similar to that in diabetic cardiomyopathy. To this end, we have focused on the peroxisome proliferator-activated receptor a (PPARa), a nuclear receptor transcription factor that activates cardiac fatty acid (FA) utilization pathways. Transgenic mice that over-express PPARa in a cardiac-specific manner (MHC-PPARa mice) have been generated. Because PPARa plays a critical role in regulating the expression of genes encoding cellular FA utilization enzymes, it is predicted that rates of FA import and oxidation will be increased in the hearts of MHC-PPARa mice, which in turn may lead to cardiac hypertrophy, dysfunction and ultimately failure. The specific aims of this proposal are 1) To characterize the metabolic phenotype of MHC-PPARa mice. 2) To characterize cardiac structure and function in MHC-PPARa mice. 3) To compare the myocardial phenotype of MHC-PPARa mice to the streptozotocin-induced model of diabetic cardiomyopathy and to determine the role of altered substrate utilization in the genesis and severity of cardiac dysfunction.