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.

性状（由申请方提供）：大肠埃希菌O157：H7相关 溶血性尿毒综合征（HUS）仍然是一个具有挑战性的医学问题。 广泛的血栓形成，伴随纤维蛋白溶解抑制， 肾损伤的最早迹象。此外，血栓形成趋势 预测随后发生的溶血尿毒综合征的严重程度。很可能是严重的内皮损伤 在肾损伤导致溶血尿毒综合征之前这种损伤是可以研究的，而且， 可能是为了减轻其影响。 在这项资助中，将研究受感染儿童的血栓形成过程 强烈地。具体来说，我们将检验血栓形成 明确先于肾损伤，并且最初的纤维蛋白形成率 评价E.大肠杆菌O157：H7感染与预后相关（目的1）。到 为了进一步评估凝血损伤，我们还将检验以下假设： 第一天和第二天之间的纤维蛋白净间隔积累 观察可预测这种感染的结果，并且随时间变化 在血栓形成前动力学基础的病理生理级联反应，导致 HUS的发展（目标2）。 我们还将使用我们独特的人口来检验假设，即（a） 补体系统的激活程度可预测儿童 E.大肠杆菌O157：H7感染，和（B）一种或多种因子H基因多态性， 与此相关的结果（目标3）。最后，由于内皮细胞 可能是关键的进化HUS，我们将测试的假设， 循环内皮细胞浓度之间的差异， 受感染的儿童预测结果。我们还将检验辅助假设 这些细胞表达与其原位损伤相关的蛋白质， 激活（目标4）。 一个独特的网络已经组装，以确定儿童的风险发展 HUS平均在HUS发展前三天。这是一个不充分的 研究，但绝对合适的模型，毒素相关的HUS。这个网络 将与混凝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 生物学该项目旨在更全面地了解级联领导 到HUS，并与此知识，成功地阻断这一进程。