MECHANISM OF DIABETIC CARDIOMYOPATHY

本项目将研究导致实验动物和糖尿病患者左心室功能障碍发展的细胞事件。糖尿病与心肌病有关，其部分特征是舒张期舒张功能受损。在以前的动物研究中，我们已经定义了这种肌病的生化特征，表明慢性蛋白激酶C激活和随后的细丝蛋白肌钙蛋白I磷酸化是适应不良的核心，并且该过程可以通过用AT 1受体拮抗剂治疗来消除。本申请将扩展这些观察。提出了两条平行的调查路线：1。将在糖尿病大鼠和小鼠中进行研究，以确定薄肌丝蛋白的转录和翻译后修饰对分离纤维的松弛性质和收缩动力学的影响。这些将包括肌钙蛋白I交换实验，在皮肤纤维，以建立功能的重要性，肌钙蛋白I磷酸化和转基因小鼠的研究表达肌钙蛋白I蛋白突变的PKC网站。2.将对从糖尿病患者心肌中分离的心细胞进行研究，以确定人类心脏病中是否存在相同的生化和机械异常。希望这种多管齐下的方法将允许将基本的实验观察扩展到临床实践。

This project will investigate cellular events that lead to the development of left ventricular dysfunction in experimental animals and patients with diabetes mellitus. Diabetes mellitus is associated with a cardiomyopathy characterized in part by impaired diastolic relaxation. In previous animal studies, we have defined biochemical features of this myopathy that suggest that chronic protein kinase C activation and subsequent phosphorylation of the thin filament protein, troponin I, is central to the maladaptation and also that this process can be abrogated by treatment with an AT1 receptor antagonist. The present application will extend these observations. Two parallel lines of investigation are proposed: 1. Studies in diabetic rats and mice will be performed to establish the effects of transcriptional and post-translation modification of thin myofilament proteins on the relaxation properties and contraction kinetics of isolated fibers. These will include troponin I exchange experiments in skinned fibers to establish the functional of significance of TnI phosphorylation and also studies in transgenic mice expressing TnI protein with a mutated PKC site. 2. Studies will be performed on cardiocytes isolated from the myocardium of patients with diabetes in order to establish whether the same biochemical and mechanical abnormalities are present in human heart disease. It is hoped that this pronged approach will allow the extension of a fundamental experimental observation to clinical practice.