Dysregulated fat utilization in diabetic cardiomyopathy

描述：(申请人？S摘要)：心功能不全发生在较高水平 糖尿病患者的发病率，即使是危险因素，如冠状动脉 动脉疾病，都被考虑在内。这项提案旨在测试 假设心肌脂肪酸摄取和氧化速度过快 导致类似于糖尿病心肌病的病理性重构。至 为此，我们重点研究了过氧化物酶体增殖物激活受体a。 激活心脏脂肪的核受体转录因子(PPARa) 酸(FA)利用途径。在小鼠体内过表达PPARa的转基因小鼠 心脏特异性方式(MHC-PPARa小鼠)已经产生。因为PPARA 在调节编码细胞的基因的表达方面起着关键作用 FA利用酶，预测FA的进口和氧化速度 将在MHC-PPARa小鼠的心脏中增加，这反过来可能导致 心肌肥大，功能障碍，最终衰竭。的具体目标 本研究的目的是：1)研究MHC-PPARa小鼠的代谢表型。 2)研究MHC-PPARa小鼠的心脏结构和功能。3)至 MHC-PPARa小鼠和小鼠心肌表型的比较 链脲佐菌素诱导的糖尿病心肌病变模型的建立 底物利用改变在心脏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.