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（由申请方提供）：本提案的总体目标是进一步开发和验证肠出血性大肠杆菌的新动物模型。大肠杆菌（EHEC）感染，我们最近的特点。我们将使用本实验室开发的模型来研究溶血性尿毒综合征（HUS）的发病机制，重要的是开发治疗方案，以预防和治疗EHEC疾病。产志贺毒素E.大肠杆菌（STEC）菌株是通过摄入未充分煮熟的肉类或其他受污染的食物而获得的。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，并可能诱发致命性HUS，其特征为微血管病性溶血性贫血、血小板减少症和急性肾衰竭。E.大肠杆菌O 157：H7感染的事实表明，约6%的感染者（尤其是儿童）会因原发性肠出血性大肠杆菌感染而出现溶血性尿毒综合症，其中约25%的患者会出现进行性肾病。肠出血性大肠杆菌菌株产生与志贺菌滋贺毒素密切相关的称为志贺样毒素（Stx 1和Stx 2）的强效蛋白毒素。肠出血性大肠杆菌感染最严重的肠道和肾脏表现是由毒素介导的血管内皮损伤引起的，伴随组织水肿、炎性浸润、促炎细胞因子产生、凝血途径诱导和导致的血管血栓。目前，只有支持性护理可用于预防肠出血性大肠杆菌感染的严重和经常致命的并发症的发展。E.大肠杆菌O 157：H7和其他STEC引起的出血性腹泻、HUS和血小板减少症仍不完全清楚，部分原因是缺乏合适的动物模型。将制定有针对性的干预策略来治疗HUS，并帮助确定HUS发病机制的可操作性。该提案的具体目标1和2是通过以下方式进一步表征EHEC感染的荷兰带状（DB）兔模型：1）定义在兔中EHEC诱导的HUS中可操作的重要病理生理事件，并采用治疗方式来中断这些导致HUS的不良事件; 2）测试被动施用免疫球蛋白或靶向单克隆抗体预防EHEC疾病的能力。 肠出血性大肠大肠杆菌（EHEC）O 157：H7是美国出血性腹泻的最常见的感染原因，并且大约6%的感染者，特别是儿童，发展为溶血性尿毒综合征（HUS）作为原发性EHEC感染的后遗症。这项建议的总体目标是进一步开发和验证我们最近表征的肠出血性大肠杆菌感染的新动物模型。我们将利用该模型研究HUS的发病机制，并重要地开发预防和治疗EHEC疾病的治疗方案。