Regulation of TLR Signals and IBD by A20

A20 对 TLR 信号和 IBD 的调节

• 批准号: 7273513
• 负责人: DAVID L. BOONE
• 金额: $ 12.18万
• 依托单位: UNIVERSITY OF CHICAGO
• 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 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7273513
• 关键词: Cell Lineage; Cells; Data; Development; Enzymes; Hematopoietic; Inflammatory; Inflammatory Response; Intestinal Mucosa; Ligands; MAP Kinase Gene; Mediator of activation protein; Microbe; Modification; Mucositis; Mus; NF-kappa B; Pathway interactions; Peptidoglycan; Process; Proteins; Receptor Signaling; Regulation; Role; Signal Pathway; Signal Transduction; Signaling Protein; Source; TNF gene; Testing; Toll-like receptors; Ubiquitin; cell type; commensal microbes; cytokine; macrophage; microbial; microbicide; pathogen; response; ubiquitin ligase

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由哺乳动物Toll样受体（TLR）启动，所述TLR识别微生物的保守组分，例如LPS或肽聚糖，并通过NF-kB和MAPK途径发出信号以产生杀微生物剂和促炎剂。我们以前已经证明，A20是必要的终止TNF诱导的NF-κ B和A20-/-小鼠发展IBD。最近，我们发现了令人惊讶的事实，即A20-/- x TNFRI-/-和A20-/- x TNF-/-小鼠可以发展IBD。这一初步观察表明，除了其在调节TNF诱导的NF-κ B中的重要作用外，A20对于调节导致IBD的TNF非依赖性过程必须是必不可少的。在这方面，我们已经发现A20-/-小鼠对LPS和其他TLR配体具有高反应性。TLR信号转导涉及信号转导蛋白的非蛋白体泛素化，我们已经发现A20对泛素化蛋白具有酶活性。因此，我们的假设是，A20对信号蛋白泛素化的修饰对于TLR诱导的细胞信号的正常调节是必不可少的，并且A20对TLR信号传导的调节防止导致IBD的过度粘膜炎症。为了验证这一假设，我们将：（1）检查A20在IBD中的TNF非依赖性作用;（2）检查A20在IBD中调节TLR信号的作用;和（3）确定A20是否和如何作为TLR信号的重要调节剂起作用