Novel Therapeutics for Diabetic Cardiomyopathy

描述（由申请人提供）： 糖尿病是一种流行病，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，其中主要原因是冠状动脉疾病。糖尿病患者患有糖尿病性心肌病，与高血压或冠状动脉疾病的血管效应无关。这表明，心肌细胞本身存在可能引起与糖尿病相关的有害心脏重塑的因素。糖尿病性心肌病是由脂肪酸代谢改变、高胰岛素血症和高血糖症引发的。糖尿病性心肌病涉及信号传导和代谢的复杂变化，其可在多个水平上调节：1）通过受体/效应物表达和定位的差异调节改变细胞信号传导; 2）改变线粒体功能和动力学; 3）改变核活性，导致病理基因表达，其可最终影响后两个因素。因此，膜/细胞质信号传导、线粒体和细胞核可以被定义为限制心脏适应糖尿病应激的能力并提供新的治疗靶点的三个控制点。在这三个位点的共同分子调节剂尚未确定。信号转导中的一个新兴观点表明，信号分子作为动态的、空间组织的多蛋白复合物存在于质膜的富脂微区中，在基础或刺激条件下连续形成和解离。小窝是富含胆固醇和鞘脂的微环境，其形成质膜的显微镜下不同的烧瓶样内陷。我们的新的初步数据表明，心脏特异性小窝蛋白-3过表达（Cav-3 OE）通过调节膜/细胞质信号传导、线粒体和细胞核的功能，在II型糖尿病模型中保护心脏免受糖尿病心肌病的影响。我们假设小窝蛋白在膜/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理解，以提供更直接的治疗靶向。提出了以下目标：目标1：确定小窝蛋白在膜/胞质信号传导中的作用以及膜靶向小窝蛋白表达在糖尿病心肌病进展中的治疗潜力。目标二：确定小窝蛋白在线粒体功能和动力学中的作用，以及糖尿病心肌病进展中靶向小窝蛋白表达的治疗潜力。目标3：确定小窝蛋白在核膜稳定性中的作用，基因表达的调节，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.