Regulation of Hepatic Repair Response by Metabolites of the Uric Acid Pathway

描述（由申请人提供）：该资助的主题是纤维化（FG）的过程，包括由肝损伤开始的不明确的步骤，并以肝硬化相关的许多变化结束。关于FG的晚期阶段有相当多的信息，但对肝损伤引发的早期阶段的了解非常有限。组织损伤导致损伤相关分子模式（DAMPs）的释放，从而启动免疫激活。我们的战略前提是肝损伤后释放的启动免疫激活的分子也会启动FG。我们已经证明，核酸通过TLR9，腺苷通过A2a受体，腺嘌呤通过Mrg受体是肝脏正常FG所必需的。在过去几年中，免疫学的一个主要发展是确定了无菌炎症（SI）的起始需要细胞质蛋白复合物（炎性体）。我们已经证明，炎性体成分是肝脏和真皮中FG所必需的。基于这一进展，我们现在提出一个假说，即炎性体途径的激活和调节是肝纤维化的核心。具体目的1：确定肝纤维化过程中DAMP和模式识别受体（PRR）活性的变化。特异性目标2：纤维形成所需的TLR9和炎性体成分的分子和细胞定位。具体目标3：腺苷受体2a和HIF介导的肝纤维化炎性小体途径的调节这将提供以下方面的详细信息：1)肝纤维化中DAMPs和TLR激动剂的释放范围和时间，以及它们在KC和HSC中的整合；2)炎性小体成分的分子和细胞需求；3)腺苷对肝纤维化中这些途径的调节。这将对我们对FG的理解产生直接的机制影响，并为在肝脏疾病中使用TLR和腺苷受体拮抗剂作为抗纤维化药物提供有价值的信息。肝纤维化是一个非常重要的问题，我们提出了一种新的方法来了解肝损伤后肝纤维化的发生。

DESCRIPTION (provided by applicant): The topic of this grant is the process of fibrogenesis (FG) which encompasses poorly defined steps initiated by liver injury, and ends with the many changes associated with cirrhosis. There is considerable information on the later stages of FG, but very limited understanding of the early steps triggered by liver injury. Tissue injury results n the release of damage associated molecular patterns (DAMPs) which initiate immune activation. Our strategic premise is that molecules released after liver injury which initiate immune activation also initiate FG. We have demonstrated that nucleic acids via TLR9, adenosine via the A2a receptor, and adenine via the Mrg receptor are required for normal FG in the liver. A major development in immunology over the last several years has been identification of the requirement of a cytosolic protein complex (inflammasome) for the initiation of sterile inflammation (SI). We have demonstrated that inflammasome components are required for FG in the liver and dermis. Based on this progress we are now proposing the hypothesis that activation and regulation of inflammasome pathways is central to hepatic fibrogenesis. Specific aim 1: Identify changes in DAMP, and pattern recognition receptor (PRR) activity during liver fibrogenesis. Specific aim 2: Molecular and cellular localization of TLR9 and inflammasome components required for fibrogenesis. Specific aim 3: Adenosine receptor 2a and HIF mediated regulation of inflammasome pathways in liver fibrogenesis This will provide detailed information on 1) range and timing of release of DAMPs and TLR agonists in FG, and their integration by KC and HSC 2) molecular and cellular requirement of inflammasome components, and 3) regulation by these pathways in hepatic FG by adenosine. This will have a direct mechanistic impact on our understanding of FG, and provide valuable information on the use of TLR and adenosine receptor antagonists as anti-fibrotics in liver diseases. Liver fibrosis is a very significant problem and we have proposed a novel approach to understand it's initiation after liver injury.