Role of chitinase-3-like-1 (Chi3l1) in acetaminophen-induced liver injury

项目摘要 本研究的目的是明确几丁质酶-3-like-1（Chi 3l 1）在肝血小板聚集中的作用 在对乙酰氨基酚（APAP）诱导的肝损伤（AILI）过程中，并评估靶向Chi 3l 1的潜力， 治疗AILI。APAP过量是美国急性肝衰竭的最常见原因， 迫切需要开发新的救生解毒剂。先前的研究表明， 血小板聚集和肝内凝血在加重AILI中起重要作用。我们最近的数据 研究表明，在APAP过量后，Chi 3l 1在小鼠和人类的肝脏中上调。Chi 3l 1-/-小鼠 出现了减弱的AILI和肝内凝血，无明显的血小板聚集， 与WT小鼠形成鲜明对比。我们鉴定了CD 44作为Chi 3l 1的受体，并发现在所有CD 44- 在肝脏表达细胞中，Chi 3l 1/CD 44的相互作用仅发生在枯否细胞上，这起着关键作用， 血小板聚集。这些发现导致我们假设Chi 3l 1通过CD 44信号传导， 枯否细胞在APAP诱导的肝血小板聚集和肝损伤中起关键作用， Chi 3l 1可作为AILI的治疗靶点。我们提出三个具体目标， (1)探讨CD 44在Chi 3l 1介导AILI病理效应中的重要作用。（2）阐明CD 44在AILI发病机制中的作用。 Chi 3l 1/CD 44轴介导枯否细胞诱导的肝血小板聚集的机制，（3）靶向 Chi 3l 1治疗AILI。

PROJECT SUMMARY The goal of this proposal is to define the role of chitinase-3-like-1 (Chi3l1) in hepatic platelet accumulation during acetaminophen (APAP)-induced liver injury (AILI) and to evaluate the potential of targeting Chi3l1 for the treatment of AILI. APAP overdose represents the most frequent cause of acute liver failure in the U.S. and developing new life-saving antidotes is critically needed. Previous studies have demonstrated that hepatic platelet accumulation and intrahepatic coagulation play an important role in exacerbating AILI. Our recent data revealed that Chi3l1 was upregulated in the liver of mice and humans after APAP overdose. The Chi3l1-/- mice developed attenuated AILI and intrahepatic coagulation with no apparent platelet accumulation, which is in stark contrast to WT mice. We identified CD44 as a receptor for Chi3l1, and found that among all CD44- expressing cells of the liver, Chi3l1/CD44 interaction only occurred on Kupffer cells, which played a critical role in platelet accumulation. These findings led to our hypothesis that Chi3l1, signaling through CD44 on Kupffer cells, plays a critical role in APAP-induced hepatic platelet accumulation and liver injury and that Chi3l1 may serve as a therapeutic target for the treatment of AILI. We propose three specific aims to (1) Investigate the critical role of CD44 in mediating the pathological effects of Chi3l1 in AILI, (2) Elucidate the mechanism by which Chi3l1/CD44 axis mediates Kupffer cell-induced hepatic platelet accumulation, (3) Target the Chi3l1 for the treatment of AILI.