Complement in the Vascular Complications of Diabetes

描述（由申请人提供）： 该提案的主要目标是研究糖化人CD 59作为血管糖尿病并发症的替代生物标志物和预测因子，特别关注糖尿病肾病和外周及心血管疾病。CD 59是一种关键的补体调节膜蛋白，其特异性抑制补体的膜攻击复合物（MAC）的形成，所述膜攻击复合物是触发刺激细胞增殖、炎症和血栓形成的生长因子和细胞因子的释放的跨膜孔。人CD 59通过糖化失活，因为其活性位点含有由氨基酸残基K41-H44形成的糖化基序，如通过人CD 59结构的NMR分析和定点诱变研究所确定。我们提出，糖基化失活的CD 59导致首先增加MAC沉积在糖尿病组织，然后增加MAC诱导的生长因子和细胞因子的释放，协同与其他高血糖诱导的途径，促进不同的组织损伤负责的血管并发症，表征人类糖尿病。与这一假设相一致，糖化CD 59和活化补体蛋白包括MAC在糖尿病患者的肾小球、神经、血管和失败的静脉移植物中发现，但在非糖尿病患者中未发现。重要的是，我们已经表明，可溶性形式的CD 59，糖化和非糖化，可以在人尿液和血浆中测定建立ELISA。糖化CD 59水平似乎与血糖暴露水平相关。这些广泛的初步数据使得有必要评估糖化CD 59是否代表糖尿病血管并发症的病理相关生物标志物。具体来说，我们将研究血浆和/或尿液中的糖化CD 59是否能识别出有发生糖尿病血管并发症风险的亚群（具体目标1），区别具有较高心血管疾病风险的葡萄糖耐量受损者（具体目标2），并预测发生糖尿病肾病的风险（具体目标3）和/或外周旁路手术后静脉移植失败的风险（具体目标4）。这些特定目标的成功实现将为糖尿病血管并发症提供一种新的生物标志物;它也将为早期治疗和预防这些糖尿病并发症开辟新的途径。

DESCRIPTION (provided by applicant): The major goal of this proposal is to investigate glycated human CD59 as a surrogate bio-marker and predictor of vascular diabetic complications, with special focus on diabetic nephropathy and peripheral and cardio-vascular disease. CD59 is a key complement regulatory membrane protein that specifically inhibits formation of the membrane attack complex of complement (MAC), a transmembrane pore that triggers the release of growth factors and cytokines that stimulate cell proliferation, inflammation and thrombosis. Human CD59 is inactivated by glycation because it contains in its active site a glycation motif formed by amino acid residues K41-H44, as determined by NMR analysis of the human CD59 structure and site directed mutagenesis studies. We proposed that glycation-inactivation of CD59 leads first to increased MAC deposition in diabetic tissues and then to increased MAC-induced release of growth factors and cytokines that synergistically with other hyperglycemia induced pathways promote the diverse tissue damage responsible for the vascular complications that characterize human diabetes. Consistent with this hypothesis, glycated CD59 and activated complement proteins including MAC are found in glomeruli, nerves, blood vessels and failed vein grafts from diabetic but not from nondiabetic patients. Importantly, we have shown that a soluble form of CD59, both glycated and non-glycated, can be measured in human urine and plasma by established ELISAs. Glycated CD59 levels seem to correlate with the level of glycemic exposure. These extensive preliminary data make it imperative to assess whether glycated CD59 represents a pathogenically relevant biomarker of diabetic vascular complications. Specifically we will investigate whether glycated CD59 in plasma and/or urine identifies sub-populations at risk of developing vascular complications of diabetes (Specific Aim 1), discriminates persons with impaired glucose tolerance who have a higher risk of cardiovascular disease (Specific Aim 2), and predicts the risk of developing diabetic nephropathy (Specific Aim 3) and/or the risk of vein graft failure after peripheral by-pass surgery (Specific Aim 4). Successful accomplishment of these Specific Aims will provide a novel biomarker of diabetic vascular complications; it will also open new avenues for the early treatment and perhaps prevention of those diabetic complications.