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An enterotoxigenic E. coli protein that antagonizes the NF-kappaB pathway

一种拮抗 NF-kappaB 通路的产肠毒素大肠杆菌蛋白

基本信息

批准号：
8891351
负责人：
Philip Ross Hardwidge
金额：
$ 22.5万
依托单位：
KANSAS STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-01 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8891351
关键词：
Anti-Inflammatory Agents Anti-inflammatory Autoimmune Diseases Autoimmune Process Award Bacterial Toxins Biochemical Biochemical Genetics Cancer Etiology Cells Clathrin Data Development Disease Endocytosis Enteral Escherichia coli Escherichia coli Proteins Fractionation Future Genetic Health Heating Host Defense Immune system Inflammatory Inflammatory Bowel Diseases Malignant Neoplasms Mammalian Cell Mass Spectrum Analysis Mediating Monoclonal Antibodies Mutagenesis NF-kappa B Pathway interactions Pharmaceutical Preparations Proteins Regulation Research Rheumatoid Arthritis Signal Pathway Signal Transduction Techniques Tumor Necrosis Factor-alpha Ubiquitination Virulence Factors Work base cytokine enteric pathogen enterotoxigenic Escherichia coli genetic approach genetic regulatory protein improved inhibitor/antagonist interest novel pathogen prevent research study transcription factor tumor necrosis factor-alpha inhibitor uptake

项目摘要

DESCRIPTION (provided by applicant): Tumor necrosis factor-alpha (TNF) is an important cytokine regulator of the immune system. Its dysregulation is implicated in causing cancer, inflammatory bowel disease, and other systemic inflammatory disorders, including rheumatoid arthritis. TNF activity leads to the activation of pro inflammatory pathways regulated by the transcription factor NF-κB. TNF inhibitors and monoclonal antibodies are used to treat many of these autoimmune and inflammatory diseases, though with limited efficacy. Significant need exists toward improving anti-TNF based therapies. Enteric bacterial pathogens have evolved mechanisms to subvert efficiently the pro-inflammatory host defenses. Motivated by the need to discover anti-inflammatory compounds that could be developed to treat autoimmune disorders, cell-free supernatants were screened from various enteric pathogens for their ability to inhibit TNF activation of the NF-κB pathway. It was discovered that entero oxigenic Escherichia coli (ETEC) secretes a heat-stable protein that efficiently blocks the host NF-κB signaling pathway induced by TNF. This proposal will use a combination of biochemical and genetic approaches to identify this TNF antagonist and to subsequently characterize its mechanism of action. In Specific Aim1, a combination of transposon mutagenesis, biochemical fractionation, and mass spectrometry techniques will be used to identify the TNF antagonist and the genetic locus on which it is encoded. In Specific Aim 2, the interaction of the TNF antagonist with the host ubiquitination machinery and with NF-κB regulatory proteins will be characterized. Identifying and characterizing this ETEC protein may advance the future development of novel anti- inflammatory compounds.

描述（由申请人提供）：肿瘤坏死因子-α（TNF）是免疫系统的重要细胞因子调节剂。它的失调与引起癌症、炎症性肠病和其他全身性炎症性疾病（包括类风湿性关节炎）有关。TNF活性导致促凋亡蛋白的激活，转录因子NF-κB调节的炎症途径。TNF抑制剂和单克隆抗体被用于治疗许多这些自身免疫性和炎性疾病，但疗效有限。对于改善基于抗TNF的疗法存在显著需求。肠道细菌病原体已经进化出有效破坏促炎宿主防御的机制。出于发现可开发用于治疗自身免疫性疾病的抗炎化合物的需要，从各种肠道病原体中筛选无细胞上清液，以确定其抑制TNF活化自身免疫性疾病的能力。 NF-κB通路。研究发现，肠产氧大肠杆菌（ETEC）分泌一种热稳定蛋白，能有效阻断TNF诱导的宿主NF-κB信号通路。该建议将使用生物化学和遗传学方法的组合来鉴定这种TNF拮抗剂，并随后表征其作用机制。在特异性Aim 1中，将使用转座子诱变、生化分级分离和质谱技术的组合来鉴定TNF拮抗剂及其编码的遗传基因座。在特定目的2中，将表征TNF拮抗剂与宿主泛素化机制和NF-κB调节蛋白的相互作用。鉴定和表征这种ETEC蛋白可能会促进未来新型抗炎化合物的开发。