Pathophysiology of Childhood Hemolytic Uremic Syndrome

简介(申请人提供)：与O157：H7相关的大肠埃希菌 溶血性尿毒症综合征(HUS)仍然是一个具有挑战性的医学问题。 广泛的血栓形成，伴随着纤溶抑制 肾脏受损的最早迹象。此外，血栓形成的趋势 预测随之而来的HUS的严重程度。据推测，这是一次大规模的内皮损伤 在肾损伤导致HUS之前。这个伤是可以研究的，而且， 有可能是因为它的影响减弱了。 在这项资助中，将研究受感染儿童的血栓形成过程。 紧锣密鼓。具体地说，我们将测试血栓形成的假设 显然是肾损伤的先兆，而且初始时的纤维蛋白生成率 对O157：H7大肠杆菌感染的评估与结果有关(目标1)。至 进一步评估凝血损伤，我们还将检验假设 第一天和第二天之间纤维蛋白的净间隔积累 观察预测了这种感染的结果，以及依赖于时间的变化 血栓前动力学是导致血栓形成的病理生理级联反应的基础 HUS的发展(目标2)。 我们还将使用我们独特的人口来测试以下假设：(A) 补体系统的激活程度可预测儿童的预后 大肠杆菌O157：H7感染，以及(B)一个或多个因子H基因多态性是 与这一结果相关(目标3)。最后，因为内皮细胞是 可能在HUS的演变中起关键作用，我们将测试以下假设 中国人循环内皮细胞浓度的差异 受感染的儿童可以预测结果。我们还将检验辅助假设。 这些细胞表达的蛋白质似乎与其原位损伤或 激活(目标4)。 已经组建了一个独特的网络来识别有发育不良风险的儿童 HUS在HUS发生前平均三天。这是一个不充分的 研究了毒素相关HU的模型，但绝对合适。这个网络 将与凝血领域的调查专业知识相结合 评估、补体病理生理学和遗传学以及内皮细胞 生物学。该项目寻求对梯级领导的更完整的理解 对于HUS，以及有了这些知识，成功地阻止这一进程。

DESCRIPTION (provided by applicant): Escherichia coli O157:H7-associated hemolytic uremic syndrome (HUS) remains a challenging medical problem. Extensive thrombogenesis, with accompanying fibrinolysis inhibition, precede the earliest indications of renal injury. Trends in thrombogenesis moreover predict the severity of ensuing HUS. Presumably, a massive endothelial injury before renal injury leads to HUS. This injury is amenable to study, and, possibly, to the attenuation of its effects. In this grant, the thrombogenic process in infected children will be studied intensively. Specifically, we will test the hypotheses that thrombogenesis clearly precedes renal injury, and that the rate of fibrin formation on initial assessment of E. coli O157:H7 infections is associated with outcome (Aim 1). To further assess the coagulation lesion, we will also test the hypotheses that net interval accumulation of fibrin between the first and second day of observation predicts outcome of this infection, and that time-dependent changes in prothrombotic kinetics underlie the pathophysiologic cascade leading to the development of HUS (Aim 2). We will also use our unique population to test the hypotheses that (a) the degree of activation of the complement system predicts outcome in children with E. coli O157:H7 infection, and (b) one or more factor H gene polymorphisms is associated with this outcome (Aim 3). Finally, because the endothelial cell is likely to be critical in the evolution of HUS, we will test the hypothesis that differences between the concentration of circulating endothelial cells in infected children predict outcome. We shall also test the subsidiary hypothesis that these cells express proteins plausibly related to their in situ injury or activation (Aim 4). A unique network has been assembled to identify children at risk of developing HUS an average of three days before HUS develops. This is an inadequately studied, but absolutely appropriate, model for toxin-related HUS. This network will be amalgamated with investigative expertise in the fields of coagulation assessment, complement pathophysiology and genetics, and endothelial cell biology. The project seeks a more complete understanding of the cascade leading to HUS, and, with this knowledge, the successful interdiction of this process.