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Survivin in Endothelial Hyperglycemia

内皮高血糖中的生存素

基本信息

批准号：
7379874
负责人：
JIAN LI
金额：
$ 21.25万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-08-01 至 2010-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7379874
关键词：
Address Apoptosis Apoptotic Applications Grants Area Attenuated Binding Binding Proteins Blood Vessels Caspase Cell Death Cell Proliferation Cell Survival Cells Complex Condition Development Diabetes Mellitus Diabetic mouse Dominant-Negative Mutation Endothelial Cells Functional disorder Glucose Heart Homeostasis Hyperglycemia Hyperglycemic Mice Infarction Knockout Mice Laboratories Mediator of activation protein Metabolic Metabolism Mus Myocardial Infarction Numbers Pathogenesis Pathway interactions Play Proliferating Protein Family Proteins Publishing Purpose Reaction Regulation Research Risk Factors Role Sodium Streptozocin Testing To specify Vascular Endothelial Cell Vascular Endothelium angiogenesis attenuation carcinogenesis improved in vivo inhibitor of apoptosis protein 2 inhibitor-of-apoptosis protein inhibitor/antagonist insight response survivin symporter

项目摘要

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.

描述（由申请人提供）：血管内皮功能障碍被认为是糖尿病发病机制中的重要因素。高血压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，与抗凋亡、血管生成和肿瘤发生有关。我们的实验室和其他实验室已经证明，在内皮细胞中，高血糖会减弱Survivin的表达。我们最近鉴定了Survivin结合蛋白，包括钠-葡萄糖协同转运蛋白-2（SGLT-2），其在高糖条件下与内皮细胞中的Survivin结合。我们推测，高血糖内皮细胞中Survivin的衰减是由Survivin与SGLT- 2或其他蛋白质形成复合物引起的。本研究的目的有两个：1）通过转导野生型和显性失活型Survivin的腺病毒载体，研究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而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来确定SGLT-2结合和抑制Survivin表达和功能的机制。2)在糖尿病小鼠模型（STZ诱导的Survivin小鼠高血糖症）中，检查减弱Survivin对内皮细胞凋亡增加和血管生成反应减少的影响，并通过给予SGLT抑制剂评价SGLT对Survivin能力的影响。这些研究将提高我们对Survivin的调节和功能后果的理解，并在治疗上保护内皮细胞免受高血糖的影响。