SHIGA LIKE TOXIN AND RENAL CELL DYSFUNCTION

尿毒症后溶血性尿毒综合征（HUS）是导致 急性肾功能衰竭的治疗方法 HUS的特征是急性 肾损伤、微血管病性溶血性贫血和血小板减少症。 肾损害主要涉及肾小球内皮细胞肿胀 以及分离、纤维蛋白积聚和血栓形成。 得明显跌幅的 肾小球滤过率（GFR）可发生无明显组织学改变， 变化，表明血管收缩剂的影响增强。 HUS是 典型地与志贺样毒素（shiga-like toxin，STT）引起的肠道感染相关 产生大肠杆菌。 毒素结合在细胞表面 鞘糖脂GB 3被内化，并抑制蛋白质合成。 上述观察结果，加上发现， 对内皮细胞有毒，让人们相信， 人肾小球内皮细胞（HGEN）是发病机制的核心 HUS肾病 然而，人们对它们如何相互作用知之甚少。 肾小球内皮细胞，尤其是人类。 此外，本发明还 关于为什么HGEN似乎是一个主要目标，我们知之甚少，或者 其他因素，在HUS。 我们发明了一种新的学习方法 HGEN。 当前的应用程序将利用这种技术， 为解决上述问题。 最后，我们对 分子生物学事件，控制细胞的敏感性，以抗肿瘤。 的 目前的项目包括提供关键信息的研究， 这个过程 因此，具体目标是：1）发展一个 人肾小球内皮细胞模型，以研究 2）测定HGEN对毒性的敏感性，包括 通过HGEN测量基线GB 3表达， 调节HGEN敏感性的炎性因子， HGEN敏感性的旁分泌和自分泌调节; 3） 确定炎症因子和炎性因子对 HGEN，包括介导SLT诱导HGEN的因素的评价 分离，HGEN调节的纤维蛋白调节的检查 积累，并分析炎症因子和炎症因子对 HGEN血管活性介质的产生;和4）克隆编码 人UDP-半乳糖：乳糖神经酰胺α 1-4-半乳糖基-转移酶， GB 3形成的限速酶。 这些研究提供 关于HGEN如何以及为什么在HUS中受损的基本信息。

Post-diarrheal hemolytic uremic syndrome (HUS) is the leading cause of acute renal failure in children. The HUS is characterized by acute renal injury, microangiopathic hemolytic anemia, and thrombocytopenia. Renal damage predominantly involves glomerular endothelial cell swelling and detachment, fibrin accumulation, and thrombosis. Marked decreases in glomerular filtration rate (GFR) can occur without obvious histologic changes, suggesting augmented vasoconstrictor influence. The HUS is typically associated with enteric infection by shiga-like toxin (SLT) producing Escherichia coli. The toxin binds to a cell surface glycosphingolipid, GB3, is internalized, and inhibits protein synthesis. The above observations, taken together with the finding that SLT is toxic for endothelial cells, have let to the belief that SLT damage to human glomerular endothelial cells (HGEN) is central to the pathogenesis of HUS renal disease. However, little is known about how SLT interacts with glomerular endothelial cells, particularly in humans. Further, little is known about why HGEN appears to be a major target of SLT, or other factors, in HUS. We have developed a new method for studying HGEN. The current application will take advantage of this technique in order to address the above issues. Finally, very little is know about the molecular biologic events that control cell sensitivity to SLT. The current project includes studies that provide crucial information about this process. Accordingly, the specific aims are: 1) development of a human glomerular endothelial cell model to study the biologic actions of SLT; 2) determination of HGEN susceptibility to SLT toxicity including measurement of baseline GB3 expression by HGEN, identification of inflammatory factors regulating HGEN SLT sensitivity, and elucidation of paracrine and autocrine regulation of HGEN SLT sensitivity; 3) determination of the biologic effects of SLT and inflammatory factors on HGEN including evaluation of factors mediating SLT-induced HGEN detachment, examination of SLT modulation of HGEN-regulated fibrin accumulation, and analysis of inflammatory factor and SLT effects on HGEN vasoactive mediator production; and 4) cloning of the gene encoding human UDP-galactose: lactosylceramide alpha 1-4-galactosyl-transferase, the rate-limiting enzyme in GB3 formation. These studies provide essential information on how and why HGEN are damaged in HUS.