The role of platelets in the pathogenesis of alcohol-associated liver disease

Abstract Mortality due to cirrhosis in the United States is increasing, driven by alcohol-associated liver disease (ALO). There is currently no specific pharmacotherapy that affects outcomes of ALO beyond short-term mortality, so new therapeutic targets are urgently needed. Platelets and intrahepatic microvascular thrombosis are increasingly recognized as key drivers of crucial biological processes within the liver, including liver fibrosis, portal hypertension, acute liver injury, and liver regeneration, in a highly context-specific manner. However, our current understanding of the mechanistic role of platelets in liver disease is greatly limited, as evidenced by the contradictory results of published studies. Platelets interact closely with liver endothelial cells to coordinate inflammation within the liver, and proinflammatory liver sinusoidal endothelial cells (LSECs) play a critical role in liver inflammation and fibrosis. In addition to its effects on the liver, alcohol also has direct pathological effects on the bone marrow and platelets themselves. The goal of this study is to define the role of platelets in the pathogenesis of ALO. We have three aims for the proposed research: 1) Define the mechanism of platelet dysfunction in alcohol-associated hepatitis; 2) Define the pathological effect of platelets in alcohol-associated hepatitis on LSECs; 3) Determine the pathological role of platelets and platelet-derived microparticles in alcohol-associated hepatitis in vivo. Our studies will begin in patients, defining specific molecular mechanisms of platelet dysfunction in alcohol-associated hepatitis using a biochemical, imaging, and bioinformatics approach. We will then utilize patient samples to determine mechanisms of pathological platelet-LSEC communication resulting in endothelial inflammation. Finally, we will utilize a preclinical model of alcohol-associated hepatitis to determine the therapeutic effect of blocking specific mechanisms of platelet-endothelial interaction in vivo This project will be conducted with the guidance and mentorship of Dr. Yasuko lwakiri, an expert in liver vascular biology, and with co-mentorship by Dr. John Hwa, an expert in platelet biology. The project will take full advantage of the significant material, clinical, and educational resources available within the Yale Liver Center and Yale University. The goal of this project is to illuminate a new paradigm of pathogenesis in alcohol­ associated liver disease, forming the basis of an independent research career.