NEW THERAPEUTICS FOR PATHOGENIC E-COLI DISEASES

致病性大肠杆菌疾病的新疗法

• 批准号: 7028893
• 负责人: TOM G OBRIG
• 金额: $ 55.84万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-03-01 至 2008-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7028893
• 关键词: Escherichia coli 0157:H7; Escherichia coli infections; RNase protection assay; antiinflammatory agents; bone marrow transplantation; cooperative study; cytokine; drug screening /evaluation; genetically modified animals; immunocytochemistry; inflammation; kidney disorder; laboratory mouse; lipopolysaccharides; lung disorder; microarray technology; purinergic receptor; shiga toxin; vascular endothelium

DESCRIPTION (provided by applicant): Pathogenic E. coli are a major cause of human diseases. Escherichia coli 0157:H7 is an "emerging infectious disease" responsible for outbreaks of food-borne illness and is the leading cause of hemolytic uremic syndrome (HUS), acute renal failure in young children. There is growing evidence that inflammatory mediators are induced in the host by E. coli 0157:H7 LPS and Shiga toxins and that both are required to cause HUS. In addition, Shiga toxins (Stx1, Stx2) produced by E. coli 0157:H7 are required for the vascular complications in HUS. At present, no effective treatments are available for E. coli 0157:H7. Thus, our long-term goal is to develop therapeutic modalities based on mechanisms by which LPS, Stx1, and Stx2 cause disease. The short-term goal is to define host inflammatory responses to E. coli LPS and Shiga toxins. In the present study, gene microarrays are employed to delineate the inflammatory response to LPS and Stx2 in mouse models of kidney and lung disease. In addition, the effectiveness of anti-inflammatory adenosine A2A receptor agonists will be tested in the murine model of LPS plus Stx1/Stx2-induced inflammation. These latter studies are based on two recent findings: 1) that a pronounced inflammatory phase is associated with LPS/Stx2 response in the kidneys of mice, and 2) that A2A receptor agonists exhibit a protective role in LPS-dependent lung inflammation and prevent LPS-induced mortality. Application of the anti-inflammatory A2A receptor agonists to E. coli 0157:H7-associated disease will be further defined using A2A receptor deficient mice and adoptive bone marrow transfer to determine the role of circulating inflammatory cells in this disease.

描述（由申请人提供）：致病性大肠杆菌是人类疾病的主要原因。大肠杆菌0157：H7是导致饮食传播疾病爆发的“新兴传染病”，是溶血性尿毒症综合征（HUS），幼儿急性肾衰竭的主要原因。越来越多的证据表明，大肠杆菌0157：H7 LPS和Shiga毒素在宿主中诱导了炎症介质，并且两者都必须引起HUS。此外，大肠杆菌0157：H7产生的Shiga毒素（STX1，STX2）是HUS中的血管并发症所必需的。目前，对于大肠杆菌0157：H7尚无有效的治疗方法。因此，我们的长期目标是根据LPS，STX1和STX2引起疾病的机制发展治疗方式。短期目标是定义对大肠杆菌LP和志贺毒素的宿主炎症反应。在本研究中，基因微阵列用于描述肾脏和肺部疾病小鼠模型中对LPS和STX2的炎症反应。此外，将在LPS Plus STX1/STX2诱导的炎症的鼠模型中测试抗炎腺苷A2A受体激动剂的有效性。这些后者的研究基于最近的两个发现：1）明显的炎症阶段与小鼠肾脏中的LPS/STX2反应有关，而2）A2A受体激动剂在LPS依赖性肺部炎症中表现出保护作用，并预防LPS诱导的死亡率。将抗炎A2A受体激动剂应用于大肠杆菌0157：将使用A2A受体缺乏小鼠和产卵骨髓转移进一步定义H7相关疾病，以确定循环炎症细胞在该疾病中的作用。