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: 6789956
• 负责人: PHILLIP I TARR
• 金额: $ 37.41万
• 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/6789956
• 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（由申请人提供）：大肠杆菌 O157: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，伴随着纤维蛋白溶解抑制，先于 肾损伤的最早迹象。此外，血栓形成的趋势 预测随后发生的 HUS 的严重程度。据推测，严重的内皮损伤 在肾损伤导致 HUS 之前。这种伤害值得研究，并且， 可能会减弱其影响。 在这笔赠款中，将研究受感染儿童的血栓形成过程 密集地。具体来说，我们将检验血栓形成的假设 明显先于肾损伤，并且最初的纤维蛋白形成率 大肠杆菌 O157:H7 感染的评估与结果相关（目标 1）。到 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纤维蛋白的净间隔积累 观察预测了这种感染的结果，并且随时间变化 促血栓动力学是病理生理级联反应的基础，导致 HUS 的发展（目标 2）。 我们还将利用我们独特的人群来检验以下假设：(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，并且(b)一种或多种H因子基因多态性是 与此结果相关（目标 3）。最后，由于内皮细胞 可能对 HUS 的进化至关重要，我们将检验以下假设： 循环内皮细胞浓度差异 受感染的儿童预测结果。我们还将检验辅助假设 这些细胞表达的蛋白质可能与其原位损伤有关，或者 激活（目标 4）。 已经组建了一个独特的网络来识别有发展风险的儿童 HUS 平均出现在 HUS 发生前三天。这是一个不充分的 研究过但绝对合适的毒素相关 HUS 模型。这个网络 将与凝血领域的研究专业知识合并 评估、补充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先的更全面的了解 到 HUS，并利用这些知识，成功阻止了这一过程。