Beta-Catenin Signaling in Liver Ischemia and Reperfusion Injury

描述(由申请人提供)：缺血再灌注损伤(IRI)引起的肝功能障碍或衰竭是肝移植后的主要问题。尽管最近在阐明肝脏IRI的可能机制方面取得了进展，但对促进肝脏IRI级联反应的分子信号通路知之甚少。我们已经证明，肝脏IRI是一种先天免疫主导的局部炎症反应。事实上，库普弗细胞是肝脏天然免疫环境的关键组成部分，是检测肝脏中入侵病原体的第一线。这些Kupffer细胞通过趋化感知和RhoA/Rho Kinase(ROCK)信号介导的定向运动来识别入侵的病原体。骨髓来源的巨噬细胞中的岩石缺乏表现出趋化性受损，并阻止炎症性疾病的发展。研究发现，在细胞迁移和趋化的调控中，ROCK是控制PTEN活性的关键介质。PTEN缺乏会结构性地增强PI3K信号，进而调节巨噬细胞的先天免疫反应。最近，我们发现？-catenin通过控制肝脏IRI中的树突状细胞(DC)程序，在调节天然适应性界面的免疫反应中发挥了关键作用，提示？-catenin信号在调节炎症疾病中DC的免疫原性和耐受性方面发挥了重要作用。然而，在肝脏IRI过程中，β-连环蛋白如何影响巨噬细胞介导的天然免疫功能尚不清楚。该方案的总体目标是了解IR应激肝脏中由？-catenin调控的细胞内信号网络。我们推测？-catenin通过以下途径调节肝脏IRI的天然免疫功能：1/通过激活PPAR？来控制ROCK信号；2/抑制MAPK通路以降低ROCK/PTEN介导的天然免疫功能。为了验证这一假说，我们提出了以下具体目标：1.分析PPAR的作用？以及MAPK信号转导通路在β-连环蛋白介导的免疫调节中的作用。2.剖析β-连环蛋白在体内调节ROCK/PTEN介导的炎症反应的分子机制。这些研究将增加我们对IR诱导的肝脏炎症中先天免疫的肝脏调节网络的理解。我们的发现将对器官移植、切除和失血性休克以及其他无菌炎症性疾病状态下局部缺血组织损伤的治疗调整具有深远的影响。

DESCRIPTION (provided by applicant): Liver dysfunction or failure caused by ischemia and reperfusion injury (IRI) is a major problem following liver transplantation. Despite recent progress in elucidating putative mechanisms of hepatic IRI, relatively little is known on the molecular signaling pathways that facilitate liver IRI cascade. We have shown that liver IRI is an innate immunity-dominated local inflammation response. Indeed, Kupffer cells, the key components of hepatic innate immune environment, represent the first line to detect the invading pathogens in the liver. These kupffer cells readily recognize invading pathogens through chemotactic sensing and directed motility mediated by RhoA/Rho kinase (ROCK) signaling. ROCK deficiency in bone marrow-derived macrophages exhibited impaired chemotaxis and prevented the development of inflammatory disease. It was found that ROCK is a key mediator to control PTEN activity in the regulation of cell migration and chemotaxis. PTEN deficiency constitutively enhanced PI3K signaling, which in turn modulated macrophage innate immune response. Recently, we have found that ?-catenin played a key role in the regulation of immune response at the innate- adaptive interface by controlling of dendritic cell (DC) programs in hepatic IRI, suggesting the emerging role of ?-catenin signaling in modulating the DC immunogenicity and tolerogenicity in the inflammatory disease. However, it remains unknown how ?-catenin may affect macrophage-mediated innate immunity during the course of hepatic IRI. The overall goal of this proposal is to understand the intracellular signaling networks regulated by ?-catenin in IR-stressed liver. We hypothesize that ?-catenin regulates innate immunity in hepatic IRI by: 1/ controlling ROCK signaling through activation of PPAR?; and 2/ inhibiting MAPK pathways to reduce ROCK/PTEN-mediated innate immune functions. To test this hypothesis, the following specific aims are proposed: 1. Analyze the roles of PPAR? and MAPK pathways on ROCK/PTEN function in the ?-catenin-mediated immune regulation in vitro. 2. Dissect the molecular mechanisms by which ?-catenin regulates ROCK/PTEN-driven inflammatory response in vivo. These studies will increase our understanding of the hepatic regulatory networks of innate immunity in IR-induced liver inflammation. Our findings will have far reaching implications for therapeutic modulation of local ischemic tissue damage in organ transplantation, resection, and hemorrhagic shock, as well as other sterile inflammatory disease states.