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

摘要 由于酒精相关性肝病，美国肝硬化的死亡率正在增加 （ALD）。目前没有特定的药物疗法可以影响酒精性肝脏病的短期预后 因此，迫切需要新的治疗靶点。血小板与肝内微血管血栓形成 越来越多地被认为是肝脏内关键生物过程的关键驱动因素，包括肝脏 肝纤维化、门静脉高压、急性肝损伤和肝再生。 然而，我们目前对血小板在肝脏疾病中的机制作用的理解非常有限， 已发表的研究结果相互矛盾，证明了这一点。血小板与肝内皮细胞相互作用密切 协调肝脏内的炎症，促炎性肝窦内皮细胞（LSECs） 在肝脏炎症和纤维化中起关键作用。除了对肝脏的影响外，酒精还具有直接的 对骨髓和血小板本身的病理影响。本研究的目的是确定 血小板在ALD发病机制中的作用 我们的研究目的有三：1）明确血小板功能障碍的机制， 酒精相关性肝炎; 2）确定酒精相关性肝炎中血小板对 3）确定血小板和血小板衍生的微粒在酒精相关性肝硬化中的病理作用。 体内肝炎。我们的研究将开始于患者，确定血小板活化的特定分子机制。 使用生化、成像和生物信息学方法研究酒精相关性肝炎的功能障碍。我们将 然后利用患者样本确定病理性血小板-LSEC通讯的机制， 内皮炎症最后，我们将利用酒精相关性肝炎的临床前模型来确定 阻断体内血小板-内皮细胞相互作用的特定机制的治疗作用 本项目将在肝脏专家岩切靖子博士的指导和指导下进行 血管生物学，并与博士约翰华，血小板生物学专家共同指导。该项目将需要 充分利用耶鲁肝脏内可用的重要材料，临床和教育资源 中心和耶鲁大学。该项目的目标是阐明酒精发病机制的新范式- 相关的肝病，形成了独立的研究生涯的基础。

Abstract Mortality due to cirrhosis in the United States is increasing, driven by alcohol-associated liver disease (ALD). There is currently no specific pharmacotherapy that affects outcomes of ALD 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 ALD. 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 Iwakiri, 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.