固有免疫细胞的Toll样受体会识别感染机体的病原微生物，活化产生大量炎症因子，炎症因子过度表达会导致机体出现内毒素休克或者败血症等一系列疾病，因此研究TLRs介导炎症反应的负向调控显得尤为重要。我们前期研究发现，E3连接酶TRIM45在TLRs活化情况下表达增加，TRIM45特异性通过蛋白酶体途径降解激酶TAK1的调控蛋白TAB2，调控TLRs介导的炎症反应。鉴于TAB2的蛋白酶体途径降解研究及TAK1激酶活性调控机制并不完善，我们将通过分子生物学、细胞生物学等手段深入研究TRIM45泛素化修饰并降解TAB2的分子机制，阐明TRIM45调控TAK1激酶活性及TLR信号通路的重要作用，并通过构建敲基因小鼠疾病模型验证TRIM45负向调控TLRs介导的炎症反应生理意义。本研究将为TLRs信号转导机制提供新的认识；为寻找基因转染防治细菌感染及内毒素休克等疾病提供理论基础。

Innate immunity is the first line to defense against pathogenic microorganisms, then produce large amounts of inflammatory cytokines, However, uncontrolled inflammation will cause various human diseases such as endotoxin shock or sepsis induced by bacteria infections, learning the negative regulation mechanisms of TLRs mediated inflammatory reaction are particularly important. Our previous study found that the expression of E3 ligase TRIM45 increased significantly when macrophages was stimulated by TLRs ligands, TRIM45 could specifically interact with and degrade TAB2 which is an regulatory protein of the kinase TAK1 through ubiquitin-proteasome pathway，then regulate the TLRs mediated inflammatory response. Given the research of TAB2 proteasome degradation pathway is not perfect, using molecular biology and cell biology methods, we will study molecular mechanisms of TAB2 ubiquitin modification and the degradation mediated by TRIM45, and clarify the mechanisms of TAK1 kinase activity regulated by TRIM45 in the TLR signaling pathways. We will also verify the physiological significance of TRIM45 negative regulating TLRs mediated inflammatory reaction using disease models in genetic mice. The purpose of this study was to provide new insight into the TLRs signal transduction mechanism and provide a new way for preventing bacterial infections, endotoxin shock and other ills.