TAK1 signaling network in tissue homeostasis

描述（由申请人提供）：TAK 1激酶是一种重要的信号传导中间体，涉及多种信号传导途径，包括TNF、IL-1和应激途径。我们最近证明，在多种上皮组织中靶向缺失TAK 1会导致细胞死亡和炎症。因此，TAK 1通过调节细胞死亡关键地参与组织稳态。尽管TAK 1对导致细胞因子产生的促炎信号传导的调节已经被很好地研究，但是调节细胞死亡的TAK 1途径仍然难以捉摸。我们已经确定TAK 1调节活性氧（ROS）的水平。TAK 1结合蛋白，TAB 1和TAB 2，差异参与TAK 1信号传导; TAB 2介导的奎宁诱导的TAK 1激活，而TAB 1介导的TAK 1激活特异性响应于应激。我们假设TAK 1通过调节ROS调节体内细胞存活和炎症，TAB 1和TAB 2调节TAK 1细胞存活信号，以响应每个蛋白质特有的刺激。长期目标是描绘TAK 1信号网络调节组织稳态。在短期内，我们的目标是确定TAK 1，TAB 1和TAB 2在ROS依赖性细胞死亡途径中的作用。该项目的结果将增强我们对组织稳态的理解，特别是ROS，细胞死亡和炎症的调节，这可能导致新的方法来改善许多与ROS相关的炎症状况。 公共卫生相关性：为了保持组织的完整性，细胞需要防止可能引起组织损伤和炎症的非计划性细胞死亡。在许多组织中，即使在正常条件下，潜在的细胞死亡诱导物如细胞因子和应激物也不断存在;然而细胞对这些诱导物具有抗性。我们已经发现，上皮组织中TAK 1激酶缺失的小鼠自发地发生与细胞死亡相关的组织损伤。这表明TAK 1激酶活性对于防止正常组织中的细胞死亡是重要的。在这个项目中，我们将确定TAK 1控制细胞死亡的机制，并确定TAK 1激酶活性如何在正常组织中调节。这些结果增强了我们对组织完整性调节机制的理解，这可能会导致新的方法来预防组织损伤相关的致病性疾病。

DESCRIPTION (provided by applicant): TAK1 kinase is an essential signaling intermediate involving multiple signaling pathways including TNF, IL-1, and stress pathways. We have recently demonstrated that the targeted deletion of TAK1 in multiple epithelial tissues causes cell death and inflammatory conditions. Thus, TAK1 is critically involved in tissue homeostasis by regulating cell death. Although TAK1 regulation of pro-inflammatory signaling leading to cytokine production has been well studied, the TAK1 pathways regulating cell death remain elusive. We have identified that TAK1 regulates the level of reactive oxygen species (ROS). TAK1 binding proteins, TAB1 and TAB2, differentially participate in TAK1 signaling; TAB2 mediates cytokine-induced TAK1 activation, whereas TAB1 mediates activation of TAK1 specifically in response to stress. We hypothesize that TAK1 regulates cell survival and inflammation in vivo by modulating ROS, and that TAB1 and TAB2 regulate TAK1-cell survival signaling in response to stimulus unique to each protein. The long-term objective is to delineate the TAK1 signaling network regulating tissue homeostasis. In short- term, we aim to determine the roles of TAK1, TAB1 and TAB2 in ROS-dependent cell death pathway. Outcomes from this project will enhance our understanding of tissue homeostasis specifically regulation of ROS, cell death and inflammation, which could lead to new approaches to improve many inflammatory conditions that are associated with ROS. PUBLIC HEALTH RELEVANCE: To maintain tissue integrity, cells need to prevent unscheduled cell death, which could induce tissue damages and inflammation. In many tissues, potential cell death inducers such as cytokines and stressors constantly present even in normal conditions; however cells are resistant to those inducers. We have found that mice having deletion of TAK1 kinase in the epithelial tissues spontaneously develop tissue damages associated with cell death. This suggests that TAK1 kinase activity is important to prevent cell death in normal tissues. In this project, we will determine the mechanism by which TAK1 controls cell death and define how TAK1 kinase activity is regulated in normal tissues. The outcomes enhance our understanding of the regulatory mechanism of tissue integrity, which could lead new approaches to prevent tissue damage-associated pathogenic conditions.