Regulation of TLR Signals and IBD by A20

描述(由申请人提供)： 对微生物病原体的炎症反应是由哺乳动物的Toll样受体(TLR)启动的，它识别微生物的保守成分，如内毒素或肽聚糖，并通过NF-kB和MAPK途径发出信号，产生杀菌和促炎因子。我们先前已经证明，A20对于终止肿瘤坏死因子诱导的核因子-kB是必不可少的，并且A20-/-小鼠发生IBD。最近，我们发现了一个令人惊讶的事实，即20-/-x TNFRI-/-和A20-/-x肿瘤坏死因子-/-小鼠可以发展为IBD。这一初步观察表明，除了在调节肿瘤坏死因子诱导的核因子-kB方面发挥重要作用外，A20对于调节导致IBD的非肿瘤坏死因子依赖的过程也必须是必不可少的。在这方面，我们发现A20-/-小鼠对内毒素和其他TLR配体具有高反应性。TLR信号涉及信号转导蛋白的非蛋白酶体泛素化，我们发现A20对泛素化的蛋白质具有酶活性。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信号的调节对导致IBD的过度粘膜炎症具有保护作用。为了验证这一假设，我们将：(1)研究A20在IBD中不依赖于肿瘤坏死因子的作用；(2)研究A20在IBD中对TLR信号的调节作用；(3)确定A20是否以及如何作为TLR信号的重要调节因子

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