Pathophysiology of Childhood Hemolytic Uremic Syndrome

儿童溶血尿毒症综合征的病理生理学

• 批准号: 6613831
• 负责人: PHILLIP I TARR
• 金额: $ 36.52万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-02-01 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6613831
• 关键词: Escherichia coli infections; bacterial cytopathogenic effect; beta globulin; child (0-11); comorbidity; complement; disease /disorder model; disease /disorder prevention /control; disease /disorder proneness /risk; early diagnosis; fibrin; genetic polymorphism; genetic susceptibility; hemolytic anemia; host organism interaction; human genetic material tag; human subject; model design /development; molecular pathology; nucleic acid sequence; pathologic process; patient oriented research; pediatrics; renal failure; thrombosis; vascular endothelium

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.

描述（申请人提供）：大肠杆菌O157：与H7相关 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，伴有纤维蛋白溶解的抑制作用 最早的肾脏损伤迹象。而且，血栓形成的趋势此外 预测随后的HUS的严重性。大概是巨大的内皮损伤 在肾脏受伤导致HUS之前。这种伤害是可以研究的，并且 可能，衰减其影响。 在这笔赠款中，将研究受感染儿童的血栓形成过程 强烈。具体而言，我们将测试血栓形成的假设 显然先于肾脏损伤，并且在初始纤维蛋白的速率 大肠杆菌O157：H7感染的评估与预后有关（AIM 1）。到 进一步评估凝血病变，我们还将检验 纤维蛋白的净间隔在第一天和第二天之间 观察预测了这种感染的结果，并且时间依赖性变化 在促脑血栓动力学中，病理生理级联是导致的 HUS的发展（AIM 2）。 我们还将利用我们独特的人群来检验（a） 补体系统的激活程度可以预测儿童的结果 大肠杆菌O157：H7感染，（b）一个或多个因子H基因多态性是 与此结果相关联（AIM 3）。最后，因为内皮细胞是 在HUS的进化中可能至关重要，我们将检验以下假设。 循环内皮细胞浓度之间的差异 受感染的儿童预测结果。我们还将检验子公司假设 这些细胞表达蛋白质与原位损伤或 激活（目标4）。 已经组装了一个独特的网络，以识别有发展风险的儿童 HUS平均在HUS发展前三天。这是一个不足的 研究了与毒素相关的HUS的研究但绝对合适的模型。这个网络 将与凝血领域的调查专业知识合并 评估，补体病理生理学和遗传学以及内皮细胞 生物学。该项目寻求对级联领导的更完整的了解 借助Hus，并且凭借这一知识，成功地阻止了这一过程。