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

几丁质酶 3-like-1 (Chi3l1) 在对乙酰氨基酚诱导的肝损伤中的作用

基本信息

批准号：
10464890
负责人：
Cynthia Ju
金额：
$ 39.43万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-17 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10464890
关键词：
Accounting Acetaminophen Acetylcysteine Acute Liver Failure Address Adhesions Antibodies Antidotes Attenuated Binding Blood Platelets CD44 gene CHI3L1 gene Cells Cessation of life Clinic Clinical Coagulation Process Concanavalin A Data Effectiveness Epitopes Goals Hepatic Hepatitis Hepatocyte Human Immunize In Vitro Individual Ingestion Kinetics Knockout Mice Kupffer Cells Lead Life Link Liver Measures Mediating Molecular Monoclonal Antibodies Mus Myelogenous Oryctolagus cuniculus Pathologic Patients Phage Display Play Process Protein Isoforms Proteomics Publishing Recombinants Research Project Grants Role Savings Serum Severities Signal Transduction Symptoms Therapeutic Therapeutic Agents Tissues United States acetaminophen overdose acetaminophen-induced liver injury antibody libraries base experimental study improved outcome in vivo insight intrahepatic intravital microscopy liver biopsy liver injury liver transplantation new therapeutic target novel therapeutics polyclonal antibody receptor screening therapeutic target

项目摘要

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.

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中发挥重要作用。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可以作为治疗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。