Proinflammatory signaling in the kidney by Shiga toxin

志贺毒素在肾脏中的促炎信号传导

• 批准号: 7516097
• 负责人: Kristin AD Sauter
• 金额: $ 4.04万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-26 至 2010-09-25
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7516097
• 关键词: Acute Kidney Failure; Animals; Binding Sites; Biological Process; Cells; Child; Data; Development; Disease; Drug or chemical Tissue Distribution; Escherichia coli EHEC; Exposure to; Gene Expression; Genes; Hemolytic Anemia; Hemolytic-Uremic Syndrome; Human; In Vitro; Inflammatory; Inflammatory Response; Kidney; Kidney Failure; Kinetics; Ligands; MAP Kinase Signaling Pathways; Measures; Mediating; Microarray Analysis; Pathway interactions; Primates; Reverse Transcriptase Polymerase Chain Reaction; Role; Serotyping; Shiga Toxin; Signal Transduction; Slice; System; Thrombocytopenia; Time; Toxic effect; Transcript; cohort; cytokine; exposed human population; globotriaosylceramide; glomerular endothelium; inhibitor/antagonist; macrophage; programs; response; transcription factor

DESCRIPTION (provided by applicant): Hemolytic-uremic syndrome (HUS), a common cause of acute renal failure in children, is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and renal failure. HUS is caused by Shiga-toxin producing E.coli of serotype O157:H7. Accumulated evidence from small animals and primates suggests that HUS is essentially a severe inflammatory disease that results from the direct effects of circulating IPS and Shiga toxin in kidneys. Although it has been established that glomerular endothelia are primary targets of Shiga toxin, macrophages appear to be additional targets that may serve to amplify the inflammatory responses. The evidence suggests that kidneys of humans and small animals display substantial differences in the tissue distribution of Gb3, the receptor for Shiga toxins. Also complicating the study of the direct inflammatory effects of LPS and Stx in the kidneys of experimental animals is the expression of increased levels of circulating cytokines, which may contribute to the inflammatory responses of the kidneys. In order to study the direct and indirect effects of Stx and LPS in a human-relevant system, I propose studies focused on precision-cut slices of human kidney in vitro. I will identify the profile of gene transcripts whose expression is increased by Stx and LPS in human kidney slices and will measure the temporal sequence of their increased expression. Inhibitors of relevant signaling pathways (MAP kinases and NFkappaB) will determine the contribution of these pathways to the development of inflammatory responses in human kidney slices. The ligands that are secreted by kidney sections in response to Stx and LPS will be identified, and their ability to elicit inflammatory responses in naive kidney slices will be determined. To investigate the potential involvement of macrophages in the development of HUS, these cells will be depleted from human kidney slices prior to exposure of slices to Stx and LPS. Taken together, these studies should contribute to an understanding of mechanisms by which Stx and LPS induce inflammatory responses in human kidneys.

描述（由申请人提供）：儿童急性肾衰竭的常见原因（HUS）的特征是微血管病性溶血性贫血，血小板减少症和肾衰竭。 HUS是由志贺 - 毒素产生的，产生了血清型O157：H7的大肠杆菌。来自小动物和灵长类动物的积累证据表明，HUS本质上是一种严重的炎症性疾病，是由于肾脏中循环IP和志贺毒素的直接影响而导致的。尽管已经确定肾小球内皮是志贺毒素的主要靶标，但巨噬细胞似乎是可以扩增炎症反应的其他靶标。证据表明，人类和小动物的肾脏在GB3的组织分布（Shiga毒素受体）的组织分布上表现出很大差异。同样使研究LP和STX在实验动物肾脏中的直接炎症作用的研究变得复杂，这表达了循环细胞因子水平升高的表达，这可能有助于肾脏的炎症反应。为了研究STX和LP在与人相关的系统中的直接和间接影响，我提出了专注于体外人类肾脏精确切片的研究。我将确定基因转录物的曲线，其表达在人肾切片中被STX和LPS增加，并将测量其增加表达的时间序列。相关信号通路（MAP激酶和NFKAPPAB）的抑制剂将确定这些途径对人肾切片中炎症反应发展的贡献。将确定肾脏切片对STX和LPS分泌的配体，并将确定它们在幼稚肾脏切片中引起炎症反应的能力。为了研究巨噬细胞在HUS发育中的潜在参与，这些细胞将在将切片暴露于STX和LPS之前从人类肾切片中耗尽。综上所述，这些研究应有助于理解STX和LP诱导人肾脏炎症反应的机制。