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）：