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

项目总结 这项提议的目的是确定几丁质酶-3-样-1(CHI3L1)在肝脏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CHI3L1的可能性 艾力的治疗。在美国，APAP过量是急性肝功能衰竭的最常见原因 开发新的救命解毒剂是当务之急。以前的研究已经证明，肝脏 血小板聚集和肝内凝血在急性肺损伤的加重中起重要作用。我们最近的数据 结果表明，在APAP过量给药后，CHI3L1在小鼠和人的肝脏中表达上调。CHI3L1-/-小鼠 发展为减弱的AILI和肝内凝血，没有明显的血小板聚集，这在 与WT小鼠形成鲜明对比。我们鉴定CD44是CHI3L1的受体，并发现在所有CD44- 在肝脏细胞中，CHI3L1/CD44的相互作用只发生在Kupffer细胞上，起着关键作用 在血小板积聚方面。这些发现导致了我们的假设CHI3L1，信号通过CD44在 Kupffer细胞在APAP诱导的肝血小板聚集和肝损伤中起关键作用 CHI3L1可能成为治疗ALI的靶点。我们提出了三个具体目标来 (1)探讨CD44在介导CHI3L1致病作用中的关键作用；(2)阐明CHI3L1在ALI发病机制中的作用 CHI3L1/CD44轴介导枯否细胞诱导的肝血小板聚集的机制，(3)靶点 治疗艾力的CHI3L1。

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.