Survivin in Endothelial Hyperglycemia

描述（申请人提供）：血管内皮功能障碍被认为是糖尿病发病的重要因素。高血糖通过增加凋亡细胞的数量和降低其增殖能力来改变内皮细胞的特征。Survivin属于凋亡抑制蛋白（inhibitor of apoptosis protein， IAP）家族，已被证明与抗凋亡、血管生成和致癌有关。我们的实验室和其他研究人员已经证明，内皮细胞中的高血糖降低了Survivin的表达。我们最近发现了Survivin结合蛋白，包括钠-葡萄糖共转运蛋白-2 (SGLT-2)，它在高糖条件下与内皮细胞中的Survivin结合。我们假设Survivin在高血糖内皮细胞中的衰减是由Survivin与SGLT- 2或其他蛋白形成复合物引起的。两个特定的目标将被解决：1)通过转染野生型和显性阴性Survivin的腺病毒构建物来评估Survivin和Survivin结合蛋白在高血糖内皮细胞中的作用，并明确Survivin结合蛋白通过阻断Survivin来促进细胞凋亡的潜在能力。具体而言，通过SGLT抑制剂和SGLT-2 SiRNA阻断SGLT-2，确定SGLT-2结合并抑制Survivin表达和功能的机制。2)在糖尿病小鼠模型（stz诱导的Survivin小鼠高血糖）中，研究减毒Survivin对内皮细胞凋亡增加和血管生成反应减少的影响，并通过SGLT抑制剂评估SGLT对Survivin能力的影响。这些研究将提高我们对Survivin的调控和功能后果的理解，并对保护内皮细胞免受高血糖的治疗具有重要意义。

DESCRIPTION (provided by applicant): Dysfunction of the vascular endothelium is regarded as an important factor in the pathogenesis of diabetes. Hyperglycemia alters the features of endothelial cells by increasing the number of apoptotic cells and reducing their ability to proliferate. Survivin belongs to the inhibitor of apoptosis protein (IAP) family, which has been shown to be associated with anti-apoptosis, angiogenesis and carcinogenesis. Our laboratory and others have demonstrated that Survivin expression is attenuated by hyperglycemia in endothelial cells. We have recently identified Survivin binding proteins including sodium-glucose co-transporter-2 (SGLT-2), which binds to Survivin in endothelial cells under high-glucose condition. We hypothesize that attenuation of Survivin in hyperglycemic endothelial cells is caused by Survivin forming a complex with SGLT- 2 or other proteins. Two specific aims will be addressed: 1) To evaluate the role of Survivin and Survivin binding proteins in hyperglycemic endothelial cells by transducing adenoviral constructs with wild-type and dominant-negative Survivin, and to specify the Survivin binding proteins' potential ability to enhance apoptosis by interrupting Survivin. Specifically, to determine the mechanism of SGLT-2 binding and inhibiting expression and function of Survivin via blocking SGLT-2 by SGLT inhibitors and SGLT-2 SiRNA. 2) To examine the effect of attenuating Survivin on increasing apoptotic and decreasing angiogenic reactions in endothelial cells in a mouse model of diabetes (STZ-induced hyperglycemia in Survivin mice) and to evaluate effects of SGLT on Survivin's capacity by administering SGLT inhibitors. These studies will improve our understanding of the regulation and functional consequences of Survivin and have significant implications in protecting endothelial cells from hyperglycemia therapeutically.