HUS Pathogenesis & clinical Outcome in an in vivo model

溶血性尿毒症发病机制

• 批准号: 7502098
• 负责人: JAMES G FOX
• 金额: $ 24.72万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-28 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7502098
• 关键词: Acute Kidney Failure; Adverse event; Animal Model; Bacteria; Blood Vessels; Child; Clinical; Coagulation Process; Colitis; Development; Diarrhea; Disease; Edema; Endothelium; Enteral; Epithelial Cells; Escherichia coli; Escherichia coli EHEC; Escherichia coli O157; Escherichia coli O157:H7; Event; Exposure to; Food; Goals; Hemolytic Anemia; Hemolytic-Uremic Syndrome; Human; Human Pathology; Immunoglobulins; Infection; Inflammatory Infiltrate; Intervention; Intestines; Kidney; Kidney Diseases; Laboratories; Meat; Mediating; Modality; Modeling; Monoclonal Antibodies; Names; Nature; Organ; Oryctolagus cuniculus; Outcome; Pathogenesis; Pathway interactions; Patients; Persons; Prevention; Process; Production; Proteins; Research Project Grants; Serotyping; Shiga Toxin; Shiga-Like Toxins; Shigella dysenteriae; Supportive care; Testing; Therapeutic; Thrombocytopenia; Thrombus; Tissues; Toxin; Treatment Protocols; Vascular Endothelium; cooking; cytokine; in vivo Model; prevent; receptor; research study; therapy design; transmission process; waterborne

DESCRIPTION (provided by applicant): The overall aim of this proposal is to further develop and validate a new animal model of enterohemorrhagic E. coli (EHEC) infection that we recently characterized. We will use this model developed in our laboratory to study pathogenesis of hemolytic uremic syndrome (HUS) and importantly to develop therapeutic regimens to prevent and treat EHEC disease. Shiga-toxin (Stx)-producing E. coli (STEC) strains are acquired by ingesting inadequately cooked meat or other contaminated foods. Person-to-person transmission is also possible. These bacteria cause hemorrhagic colitis and may induce fatal HUS characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. The serious nature of E. coli O157:H7 infection is illustrated by the fact that ~6% of those infected, particularly children, develop HUS as a sequela of the primary EHEC infection and ~ 25% of these patients develop progressive renal disease. EHEC strains produce potent protein toxins named Shiga-like toxins (Stx1 and Stx2) that are closely related to Shiga toxin of Shigella dysenteriae. The most severe intestinal and renal manifestation of EHEC infection result from toxin-mediated damage to vascular endothelium, with tissue edema, inflammatory infiltrates, proinflammatory cytokine production, coagulation pathway induction and resulting vascular thrombi. At present, only supportive care is available to prevent the development of the severe, and frequently fatal, complications of EHEC infection. The pathogenic process by which E. coli O157:H7 and other STEC evoke bloody diarrhea, HUS, and thrombocytopenia remains incompletely understood in part due to the lack of a suitable animal model. Targeted intervention strategies will be developed to treat HUS as well as help define mechanisms operable in the pathogenesis of HUS. Specific Aims 1 and 2 of the proposal are to further characterize the Dutch Belted (DB) rabbit model of EHEC infection by 1) Defining important pathophysiologic events operable in EHEC-induced HUS in rabbits and employ therapeutic modalities to interrupt these adverse events leading to HUS; 2) Testing the ability of passively administered immunoglobulin or targeted monoclonal antibodies to prevent EHEC disease. Enterohemorrhagic E. coli (EHEC) O157:H7 is the most common infectious cause of bloody diarrhea in the U.S. and approximately 6% of those infected, particularly children, develop hemolytic uremic syndrome (HUS) as a sequela of the primary EHEC infection. The overall goal of this proposal is to further develop and validate a new animal model of EHEC infection that we recently characterized. We will use this model to study the pathogenesis of HUS and importantly to develop therapeutic regimens to prevent and treat EHEC disease.

描述（由申请人提供）：该提案的总体目的是进一步开发和验证我们最近表征的肠hag型大肠杆菌（EHEC）感染的新动物模型。我们将使用该模型在我们的实验室中开发的模型来研究溶血性尿毒症综合征（HUS）的发病机理，并重要的是开发治疗方案以预防和治疗EHEC疾病。通过摄入不充分煮熟的肉或其他受污染的食物来获得产生的大肠杆菌（STEC）菌株。人与人之间的传播也是可能的。这些细菌引起出血性结肠炎，并可能诱导以微型溶血性贫血，血小板减少和急性肾衰竭为特征的致命性壳。大肠杆菌O157：H7感染的严重性是通过以下事实说明的：受感染者，尤其是儿童的患者中有6％的HUS作为原发性EHEC感染的续集，并且这些患者中约有25％发生了进行性肾脏疾病。 EHEC菌株会产生与Shigella dysenteriae的志贺氏毒素密切相关的名为Shiga样毒素（STX1和STX2）的有效蛋白毒素。 EHEC感染的最严重的肠道和肾脏表现是毒素介导的对血管内皮的损害，具有组织水肿，炎性浸润，促炎性细胞因子的产生，凝结途径诱导和导致的血管血栓。目前，仅提供支持性护理，以防止EHEC感染的严重且经常致命的并发症的发展。大肠杆菌O157：H7和其他STEC引起血腥腹泻，HUS和血小板减少症的致病过程，部分原因是缺乏合适的动物模型，部分原因是部分原因是部分原因。将制定有针对性的干预策略来治疗HUS，并有助于定义在HUS发病机理中可操作的机制。该提案的具体目的1和2是通过1）定义可在EHEC诱导的兔子中可操作的重要病理生理事件的EHEC感染的荷兰腰带（DB）兔模型，并采用治疗方式来中断这些导致HUS的不良事件； 2）测试被动施用的免疫球蛋白或靶向单克隆抗体预防EHEC疾病的能力。 在美国，肠h7肠肠胃肠炎（EHEC）O157：H7是最常见的流血性腹泻的原因，大约6％的感染者，尤其是儿童，患有溶血性尿毒症综合征（HUS）作为原发性EHEC感染的后遗症。该提案的总体目标是进一步开发和验证我们最近表征的EHEC感染的新动物模型。我们将使用该模型来研究HUS的发病机理，并重要的是开发治疗方案以预防和治疗EHEC疾病。