Novel Therapeutics for Diabetic Cardiomyopathy

糖尿病心肌病的新疗法

• 批准号: 8803350
• 负责人: Hemal H Patel
• 金额: --
• 依托单位: VA SAN DIEGO HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8803350
• 关键词: Affect; Blood Vessels; Cardiac; Cardiac Myocytes; Cause of Death; Caveolae; Caveolins; Cell Nucleus; Cell membrane; Cells; Cholesterol; Complex; Coronary Arteriosclerosis; Cytoplasm; DNA Binding; Data; Diabetes Mellitus; EFRAC; Electron Transport; Environment; Epidemic; Gene Expression; Generations; Glucose Transporter; Health; Heart; Heart Diseases; Hyperglycemia; Hyperinsulinism; Hypertension; Hypertrophy; Insulin Receptor; Laboratories; Lipids; Lipoidosis; Maintenance; Mediator of activation protein; Membrane; Membrane Lipids; Membrane Potentials; Metabolism; Mitochondria; Modeling; Molecular; Myocardial Ischemia; Non-Insulin-Dependent Diabetes Mellitus; Nuclear; Nuclear Envelope; Nuclear Structure; Pathologic; Pathology; Plasma; Play; Post-Translational Protein Processing; Process; Receptor Signaling; Regulation; Reperfusion Injury; Role; Signal Transduction; Signaling Molecule; Site; Sphingolipids; Stress; Structural Protein; Structure; Sturnus vulgaris; Testing; Therapeutic; base; caveolin-3; diabetic; diabetic cardiomyopathy; diabetic patient; fatty acid metabolism; flasks; fluidity; genetic regulatory protein; insulin signaling; new therapeutic target; novel; novel therapeutics; overexpression; protein complex; receptor; response; scaffold; therapeutic target

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.

描述（由申请人提供）： 糖尿病已成为一种流行病，预计到 2025 年将有 3 亿人患有糖尿病。心脏病是 80% 糖尿病患者的死因，其中最主要的因素是冠状动脉疾病。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影响无关。这表明心肌细胞本身存在一些促成因素，可能会引起与糖尿病相关的有害心脏重塑。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发的。糖尿病心肌病涉及信号传导和代谢的复杂变化，这些变化可能在多个层面上受到调节：1）通过受体/效应子表达和定位的差异调节来改变细胞信号传导； 2）改变线粒体功能和动力学； 3）核活性改变导致病理基因表达，最终可能影响后两个因素。因此，膜/细胞质信号传导、线粒体和细胞核可以被定义为三个控制点，限制心脏适应糖尿病应激的能力并提供新的治疗靶点。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想法表明，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含脂质的微域中，在基础或刺激条件下不断形成和解离。小凹是富含胆固醇和鞘脂的微环境，形成微观上明显的质膜烧瓶状内陷。我们的新初步数据表明，心脏特异性的 Caveolin-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，在 II 型糖尿病模型中保护心脏免受糖尿病性心肌病。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性心肌病至关重要。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，从而提供更定向的治疗靶向。提出以下目标： 目标 1：确定小窝蛋白在膜/细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 2：确定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小窝蛋白表达在糖尿病心肌病进展中的治疗潜力。目标 3：确定小窝蛋白在核膜稳定性、基因表达调节中的作用，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。