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

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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.