Regulation of TLR Signals and IBD by A20

A20 对 TLR 信号和 IBD 的调节

• 批准号: 6966480
• 负责人: DAVID L. BOONE
• 金额: $ 2.34万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6966480
• 关键词: biological signal transduction; cell population study; enteric bacteria; hematopoietic tissue; immunogenetics; inflammation; inflammatory bowel diseases; intestinal mucosa; laboratory mouse; lipopolysaccharides; mitogen activated protein kinase; nuclear factor kappa beta; pathologic process; receptor expression; tissue /cell culture; toll like receptor; tumor necrosis factor alpha; ubiquitin

DESCRIPTION (provided by applicant): The inflammatory response to microbial pathogens is initiated by mammalian Toll-like receptors (TLR) that recognize conserved components of microbes, such as LPS or peptidoglycan, and signal through NF-kB and MAPK pathways to produce microbicidal and pro-inflammatory agents. We have previously demonstrated that A20 is essential for the termination of TNF-induced NF-kB and that A20-/- mice develop IBD. More recently we have uncovered the surprising fact that A20-/- x TNFRI-/- and A20-/- x TNF-/- mice can develop IBD. This initial observation suggests that, in addition to its essential role in the regulation of TNF-induced NF-kB, A20 must be essential for the regulation of a TNF-independent process that leads to IBD. In that regard, we have found that A20-/- mice are hyper-responsive to LPS and other TLR ligands. TLR signaling involves the non-proteosomal ubiquitylation of signal transduction proteins, and we have found that A20 has enzymatic activity toward ubiquitylated proteins. Thus, our hypothesis is that modification of signal protein ubiquitylation by A20 is essential for the normal regulation of TLR-induced cellular signals and that A20 regulation of TLR signaling protects against the excessive mucosal inflammation that leads to IBD. To test this hypothesis we will: (1) Examine the TNF-independent role of A20 in IBD; (2) Examine the role of A20 regulation of TLR signals in IBD and (3) Determine whether and how A20 acts as an essential regulator of TLR signaling

描述（由申请人提供）： 对微生物病原体的炎症反应是由识别微生物（例如LPS或肽聚糖）的保守成分的哺乳动物Toll样受体（TLR）引发的，并通过NF-KB和MAPK途径发出信号，以产生微生物症和炎症剂。我们以前已经证明，A20对于终止T​​NF诱导的NF-KB至关重要，并且A20 - / - 小鼠会发展为IBD。最近，我们发现了一个令人惊讶的事实，即A20 - / - X TNFRI - / - 和A20 - / - X TNF - / - 小鼠可以开发IBD。最初的观察结果表明，除了其在调节TNF诱导的NF-KB中的重要作用外，A20对于调节导致IBD的独立TNF过程至关重要。在这方面，我们发现A20 - / - 小鼠对LPS和其他TLR配体具有超反应性。 TLR信号传导涉及信号转导蛋白的非蛋白体泛素化，并且我们发现A20具有酶促活性对泛素化蛋白。因此，我们的假设是，通过A20对信号蛋白泛素化的修饰对于正常调节TLR诱导的细胞信号至关重要，并且A20的TLR信号调节可预防导致IBD的过度粘膜炎症。为了检验这一假设，我们将：（1）检查A20在IBD中的独立于TNF的作用； （2）检查TLR信号在IBD中的A20调节的作用，（3）确定A20是否以及如何充当TLR信号的必要调节剂