Novel Therapeutics for Diabetic Cardiomyopathy

描述(由申请人提供)： 糖尿病正处于流行阶段，预计到2025年将有3亿人患有糖尿病。心脏病是80%的糖尿病患者的死因，其中冠心病是主要的致死因素。糖尿病患者的糖尿病心肌病变与高血压或冠状动脉疾病对血管的影响无关。这表明，心肌细胞本身有可能导致与糖尿病相关的有害心脏重塑的因素。糖尿病心肌病是由脂肪酸代谢改变、高胰岛素血症和高血糖引起的。糖尿病心肌病涉及信号和代谢的复杂变化，可能在多个水平上进行调节：1)通过受体/效应器的表达和定位的差异调节改变细胞信号；2)改变线粒体的功能和动力学；3)核活动改变导致病理基因表达的改变，最终可能影响后两个因素。因此，膜/细胞质信号、线粒体和细胞核可以被定义为三个控制点，它们限制了心脏适应糖尿病应激的能力，并提供了新的治疗靶点。这三个位点的共同分子调控因子尚未确定。信号转导的一个新概念认为，信号分子以动态的、空间有序的多蛋白质复合体的形式存在于质膜的富脂微区中，在基础或刺激条件下不断形成和解离。小窝是富含胆固醇和鞘磷脂的微环境，在显微镜下形成质膜上不同的烧瓶状内陷。我们新的初步数据显示，心脏特异性小窝蛋白-3过表达(Cav-3 OE)通过调节膜/细胞质信号、线粒体和细胞核的功能来保护心脏免受II型糖尿病模型中的糖尿病心肌病的影响。我们推测，小窝蛋白在膜/细胞质、线粒体和/或细胞核中的局部表达和调节活性对于保护心脏免受糖尿病心肌病的影响至关重要。小窝蛋白的靶向表达可以提供对小窝蛋白在糖尿病中的分子作用的详细了解，从而为治疗提供更直接的靶向。目的1：确定小窝蛋白在膜/细胞质信号转导中的作用，以及膜靶向小窝蛋白表达在糖尿病心肌病变进展中的治疗潜力。目的：研究小窝蛋白在线粒体功能和动力学中的作用，以及线粒体靶向表达小窝蛋白在糖尿病心肌病进展中的治疗潜力。目的：确定小窝蛋白在核膜稳定性、基因表达调控中的作用，以及核靶向小窝蛋白表达在糖尿病心肌病进展中的治疗潜力。

DESCRIPTION (provided by applicant): Diabetes is at epidemic proportions with 300 million people projected to have diabetes by 2025. Heart disease is the cause of death in 80% of diabetic patients of which the major contributing factor is coronary artery disease. Diabetics suffer from a diabetic cardiomyopathy independent of the vascular effects of hypertension or coronary artery disease. This suggests that there are contributing factors within the cardiac myocyte itself that may give rise to detrimental cardiac remodeling associated with diabetes. Diabetic cardiomyopathy is triggered by alteration in fatty acid metabolism, hyperinsulinemia, and hyperglycemia. Diabetic cardiomyopathy involves complex changes in signaling and metabolism that may be regulated at multiple levels: 1) altered cellular signaling through differential regulation of receptor/effector expression and localization; 2) altered mitochondrial function and dynamics; 3) altered nuclear activity leading t pathologic gene expression that may ultimately affect the latter two factors. As such, membrane/cytoplasmic signaling, mitochondria, and the nucleus could be defined as three control points that limit the ability of the heart to adapt to diabetic stress and offer novel therapeutic targets. A common molecular regulator at these three sites has not been identified. An emerging idea in signal transduction suggests signaling molecules exist as dynamic, spatially organized multi-protein complexes in lipid-rich microdomains of the plasma membrane continuously forming and dissociating under basal or stimulated conditions. Caveolae are cholesterol and sphingolipid-enriched microenvironments that form microscopically distinct flask-like invaginations of the plasma membrane. Our novel preliminary data show that heart-specific caveolin-3 overexpression (Cav-3 OE) protects hearts from diabetic cardiomyopathy in a model of Type II diabetes by modulating function of membrane/cytoplasmic signaling, mitochondria, and the nucleus. We hypothesize that the localized expression and regulatory activity of caveolin in the membrane/cytoplasm, mitochondria, and/or the nucleus are critical to protection of the heart from diabetic cardiomyopathy. Targeted expression of caveolin may provide a detailed understanding of the molecular role of caveolin in diabetes to provide more directed targeting of therapeutics. The following aims are proposed: Aim 1: Determine the role of caveolin in membrane/cytoplasmic signaling and the therapeutic potential of membrane-targeted caveolin expression in the progression of diabetic cardiomyopathy. Aim 2: Determine the role of caveolin in mitochondrial function and dynamics and the therapeutic potential of mitochondrial-targeted caveolin expression in the progression of diabetic cardiomyopathy. Aim 3: Determine the role of caveolin in nuclear envelope stability, modulation of gene expression, and the therapeutic potential of nuclear-targeted caveolin expression in the progression of diabetic cardiomyopathy.