TAK1 signaling network in tissue homeostasis

说明(申请人提供)：TAK1激酶是一种重要的信号中间体，涉及多个信号通路，包括肿瘤坏死因子、白介素1和应激通路。我们最近证明，在多种上皮组织中，TAK1的靶向缺失会导致细胞死亡和炎症。因此，TAK1通过调节细胞死亡在组织动态平衡中起关键作用。尽管TAK1调节促炎信号导致细胞因子的产生已经得到了很好的研究，但调节细胞死亡的TAK1通路仍然难以捉摸。我们已经发现TAK1调节ROS的水平。TAK1结合蛋白TAB1和TAB2分别参与TAK1信号转导，TAB2介导细胞因子诱导的TAK1激活，而TAB1介导TAK1在应激反应中的特异性激活。我们假设，TAK1通过调节ROS来调节体内的细胞生存和炎症，TAB1和TAB2通过对每种蛋白质特有的刺激反应来调节TAK1细胞的生存信号。长期目标是描绘调节组织内稳态的TAK1信号网络。短期内，我们的目标是确定TAK1、TAB1和TAB2在ROS依赖的细胞死亡途径中的作用。该项目的成果将加强我们对组织稳态的理解，特别是对ROS、细胞死亡和炎症的调节，这可能导致改善与ROS相关的许多炎症状况的新方法。 公共卫生相关性：为了保持组织的完整性，细胞需要防止计划外的细胞死亡，这可能会导致组织损伤和炎症。在许多组织中，潜在的细胞死亡诱导物，如细胞因子和应激源，即使在正常条件下也会持续存在；然而，细胞对这些诱导剂具有抵抗力。我们发现，在上皮组织中有TAK1激酶缺失的小鼠会自发地发生与细胞死亡相关的组织损伤。这表明，TAK1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TAK1控制细胞死亡的机制，并确定TAK1激酶活性在正常组织中是如何调节的。这些结果增强了我们对组织完整性调节机制的理解，这可能会导致预防组织损伤相关致病条件的新方法。

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.