Alcohol-related liver disease (ALD) is a prevalent clinical problem, with many knowledge gaps in the pathogenesis of ALD, including the role and regulation of inflammatory and tissue reactions. Our overarching goal is to identify key new players in alcohol-mediated effects on development and progression of liver damage and fibrosis that could translate to targeted therapies. The extracellular matrix (ECM) and ECM dyshomeostasis are known to be important in ALD. ECM is produced by resident cells in the tissue/organ and contains a diverse range of components that create a dynamic and responsive microenvironment that regulates cell and tissue homeostasis. Our previous work demonstrated diverse qualitative and quantitative alterations to hepatic ECM during experimental ALD. In toto, alterations to the hepatic ECM are mediated not only by changes in ECM production, but also by changes in ECM degradation. We and others have demonstrated that even acute liver injury causes robust hepatic ECM changes. ECM also represents a potent reservoir of cell-signaling molecules that regulate cell behavior, determine cell phenotype and cell secretome, as well as influence inflammatory tissue responses. Numerous examples exist of cells dramatically changing their structural and functional phenotype when exposed to ECM different from their existing (normal or abnormal) ECM. By extension, changes to and/or altered turnover of hepatic ECM have potential to drive phenotypic changes in disease pathogenesis and progression. Work from our group shows that a major source of signaling molecules in ECM resides within matrix bound nanovesicles (MBV). MBV are nanometer-sized, membranous vesicles uniquely-bound within the ECM network. MBV contain and protect biologically active signaling molecules (miRNAs/proteins), and are known to play a role in immunomodulation, stem/progenitor cell differentiation, and maintenance of structurally normal and functional tissues. MBV likely play a fundamental role in tissue and organ organization across species and a regulatory role in the tissue response to injury. Our exciting preliminary studies show alcohol exposure dramatically alters hepatic MBV proteome and RNA/miRNA content. Similar changes are also seen in liver MBV isolated from ALD human explant livers vs liver MBV from non-ALD patients. We also show that liver MBV from alcohol-fed mice have differential effects on macrophage polarization and activation. Most importantly our preliminary findings suggest exogenous administration of MBV can significantly reduce alcohol-associated liver damage and inflammation. We hypothesize that MBV act not only as tissue biomarkers of ALD but are also important in regulating pathogenesis and disease progression. We will test this hypothesis via the following Specific Aims: 1. To analyze liver MBV biology in ALD.; 2. To understand mechanisms of liver MBV effects in ALD; 3. To test the ability of MBV to treat experimental ALD. Impact: Successful complet...