Beta-Catenin Signaling in Liver Ischemia and Reperfusion Injury

描述（由申请人提供）：缺血和再灌注损伤（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的假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。我们已经表明，肝脏IRI是一种先天免疫主导的局部炎症反应。事实上，枯否细胞是肝脏先天免疫环境的关键组成部分，代表了检测肝脏中入侵病原体的第一线。这些库普弗细胞容易识别入侵病原体通过趋化传感和定向运动RhoA/Rho激酶（ROCK）信号转导介导的。骨髓源性巨噬细胞中ROCK的缺乏表现出趋化性受损，并阻止了炎症性疾病的发展。研究发现，ROCK是调控细胞迁移和趋化性中PTEN活性的关键介质。PTEN缺陷组成性增强PI 3 K信号传导，这反过来又调节巨噬细胞的先天免疫应答。最近，我们发现，？连环蛋白通过控制树突状细胞（DC）在肝脏IRI中的程序，在先天-适应性界面的免疫应答调节中起关键作用，这表明？连环蛋白信号传导调节炎症性疾病中DC的免疫原性和致耐受性。然而，它仍然是未知的如何？在肝IRI过程中，catenin可能影响巨噬细胞介导的天然免疫。该提案的总体目标是了解细胞内信号网络调节？- IR应激肝脏中的连环蛋白。我们假设？-连环蛋白通过以下方式调节肝脏IRI中的先天免疫：1/通过激活PPAR？控制ROCK信号传导;和2/抑制MAPK途径以降低ROCK/PTEN介导的先天免疫功能。为了验证这一假设，提出了以下具体目标：1。分析PPAR的作用？和MAPK途径对ROCK/PTEN功能的影响。连环蛋白介导的体外免疫调节。2.剖析分子机制？-连环蛋白调节ROCK/PTEN驱动的体内炎症反应。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症性疾病状态中局部缺血性组织损伤的治疗调制产生深远的影响。

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.