Beta-Catenin Signaling in Liver Ischemia and Reperfusion Injury

描述（申请人提供）：肝脏缺血再灌注损伤（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的推定机制方面取得了进展，但对促进肝脏IRI级联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，库普弗细胞是肝脏先天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道防线。这些kupffer细胞通过RhoA/Rho激酶（ROCK）信号介导的趋化传感和定向运动，很容易识别入侵的病原体。骨髓源性巨噬细胞的ROCK缺乏表现出趋化性受损，并阻止炎症性疾病的发展。发现ROCK是调控PTEN活性调控细胞迁移和趋化的关键介质。PTEN缺乏可组成性地增强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中树突状细胞（DC）程序在先天-适应性界面的免疫反应调控中发挥关键作用，提示？-catenin信号在炎症性疾病中调节DC免疫原性和耐受性的作用然而，我们仍然不知道它是如何发生的。-catenin可能影响肝脏IRI过程中巨噬细胞介导的先天免疫。本提案的总体目标是了解由？-catenin在ir应激肝脏中的表达我们假设？-catenin通过激活PPAR调控ROCK信号通路调节肝脏IRI的先天免疫；和2/抑制MAPK通路降低ROCK/ pten介导的先天免疫功能。为了验证这一假设，提出以下具体目标：1。分析PPAR的作用？和MAPK通路对ROCK/PTEN的作用？-连环蛋白介导的体外免疫调节。2. 通过什么剖析分子机制？-catenin在体内调节ROCK/ pten驱动的炎症反应。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。我们的研究结果将对器官移植、切除、失血性休克以及其他无菌炎性疾病状态下局部缺血性组织损伤的治疗调节具有深远的意义。

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.