Induction of Tissue Factor by Patient Sera in HUS

HUS 患者血清诱导组织因子

• 批准号: 7229792
• 负责人: Eric Franklin Grabowski
• 金额: $ 21.24万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7229792
• 关键词: Active Sites; Acute; Acute Kidney Failure; Adhesions; Antibodies; Beds; Biological Models; Blood; Blood Platelets; Blood flow; Child; Childhood; Clinical Trials; Coagulation Process; Coma; Commit; Condition; Coupled; Critiques; Cultured Cells; Data; Deposition; Diarrhea; Disease; Endothelial Cells; Ensure; Epithelial Cells; Escherichia coli; Event; Factor VIIa; Factor Xa; Fibrin; Foxes; Functional disorder; Gastrointestinal tract structure; Generations; Grant; Hematologist; Hemolysis; Hemolytic Anemia; Hemolytic-Uremic Syndrome; Hemophilia A; Hemostatic Agents; Human; In Vitro; Injury; Interruption; Intestines; Kidney; Kidney Failure; Laboratories; Measures; Mediating; Modeling; Necrosis; Numbers; Organ; Oryctolagus cuniculus; Pathway interactions; Patient Recruitments; Patients; Performance; Phase; Plasma; Play; Protocols documentation; Rate; Recombinants; Role; Sampling; Seizures; Series; Serum; Shiga Toxin; Shiga-Like Toxin I; Societies; Stroke; Supportive care; Surface; TFPI; Testing; Thrombocytopenia; Thromboplastin; Thrombosis; Thrombus; Tissues; Triad Acrylic Resin; Tumor Necrosis Factor-alpha; Up-Regulation; Work; activated Protein C; base; cell injury; cytokine; human TNF protein; inhibitor/antagonist; monolayer; novel; novel strategies; response

DESCRIPTION (provided by applicant): Diarrhea-positive Hemolytic Uremic Syndrome (D+ HUS) is a serious disease in children that causes hemolytic anemia, thrombocytopenia, and acute renal failure. In fact, it is the most common cause of acute renal failure in children. During the acute phase of the HUS, some 3 to 5% of patients die, while as many as 25% also suffer stroke, seizures, and/or coma. At present this condition has little established pathophysiology, aside from an association with shiga toxin produced by strains of Escherichia coli and the presence of plasma markers indicative of a prothrombotic state. We have previously demonstrated that shiga toxin significantly increases the expression of functional tissue factor (TF) by TNF-alpha-activated human glomerular endothelial cells (HGECs). Therefore, we hypothesize that increased TF activity plays an important role in the pathophysiology of HUS. Through this grant we aim 1) to demonstrate that kidney sections from a rabbit model of HUS are prothrombotic as compared to control kidney tissue; 2) to demonstrate that sera from patients with HUS augment the expression of TF, while the blood of these patients contains TF-positive circulating endothelial cells and microparticles; and 3) to use monolayers of HGECs, patient platelet adhesion/aggregation in flowing blood, and kidney from the rabbit model to test inhibitors of the TF pathway as potential therapies for HUS. These inhibitors include recombinant-TF pathway inhibitor, an antibody directed against activated factor X, recombinant-activated protein C, and active site-inhibited r-factor VIIa. A confirmation that shiga toxin and cytokines present in patient sera augment the TF pathway in our model system coupled with a demonstration that pharmacologic interruption of this pathway is both effective and feasible, will help to develop a novel, effective therapy for childhood HUS, where at present only supportive care is available. A key additional feature of this proposal is the use of our newly formed collaborative group of pediatric nephrologists to facilitate patient recruitment

描述（由申请人提供）： 腹泻阳性溶血性尿毒症综合征 (D+ HUS) 是一种严重的儿童疾病，会导致溶血性贫血、血小板减少和急性肾功能衰竭。事实上，它是儿童急性肾衰竭的最常见原因。在 HUS 急性期，约 3% 至 5% 的患者死亡，而多达 25% 的患者还患有中风、癫痫发作和/或昏迷。目前，除了与大肠杆菌菌株产生的志贺毒素以及指示血栓前状态的血浆标志物的存在有关之外，这种情况的病理生理学还没有确定。我们之前已经证明，志贺毒素可显着增加 TNF-α 激活的人肾小球内皮细胞 (HGEC) 的功能组织因子 (TF) 表达。因此，我们假设 TF 活性增加在 HUS 的病理生理学中发挥重要作用。通过这笔资助，我们的目标是 1) 证明 HUS 兔模型的肾脏切片与对照肾组织相比具有促血栓形成作用； 2) 证明HUS患者的血清增强了TF的表达，而这些患者的血液中含有TF阳性的循环内皮细胞和微粒； 3) 使用单层 HGEC、流动血液中的患者血小板粘附/聚集以及兔子模型的肾脏来测试 TF 途径的抑制剂作为 HUS 的潜在疗法。这些抑制剂包括重组 TF 途径抑制剂、针对活化因子 X 的抗体、重组活化蛋白 C 和活性位点抑制的 r 因子 VIIa。证实患者血清中存在的志贺毒素和细胞因子增强了我们模型系统中的 TF 通路，并证明药物阻断该通路既有效又可行，将有助于开发一种新颖、有效的治疗儿童 HUS 的方法，目前仅提供支持性护理。该提案的一个关键附加特征是利用我们新成立的儿科肾病专家合作小组来促进患者招募