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

摘要 在美国，由酒精相关的肝病导致的肝硬变死亡率正在上升 (ALD)。目前还没有特定的药物治疗方法可以影响ALD患者的短期预后 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学过程的关键驱动因素，包括肝脏 纤维化、门脉高压、急性肝损伤和肝再生，以高度特定的方式。 然而，我们目前对血小板在肝病中的机制作用的了解非常有限，因为 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密切相互作用 协调肝脏内的炎症，促进炎症的肝窦内皮细胞(LSECs)发挥作用 在肝脏炎症和纤维化中起关键作用。酒精除了对肝脏有影响外，还会直接 对骨髓和血小板本身的病理影响。这项研究的目标是确定 血小板在ALD发病机制中的作用 我们提出的研究有三个目的：1)明确血小板功能障碍的机制 酒精性肝炎；2)明确酒精性肝炎中血小板的病理作用 LSECs；3)确定血小板和血小板衍生微粒在酒精相关疾病中的病理作用 活体肝炎。我们的研究将在患者身上开始，确定血小板的特定分子机制 用生化、影像和生物信息学方法研究酒精相关性肝炎的功能障碍。我们会 然后利用患者样本来确定病理性血小板-LSEC通讯的机制 内皮细胞发炎。最后，我们将利用酒精相关性肝炎的临床前模型来确定 阻断体内特定的血小板-内皮相互作用机制的治疗作用 该项目将在肝脏专家岩井康子博士的指导和指导下进行 血管生物学，并由血小板生物学专家John Hwa博士共同指导。这项工程将需要 充分利用耶鲁大学肝脏提供的重要材料、临床和教育资源 中心和耶鲁大学。这个项目的目标是阐明酒精致病机制的新范式- 相关的肝病，形成了独立研究事业的基础。

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.