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：
9898894
负责人：
Cynthia Ju
金额：
$ 40.83万
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/9898894
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 Poisoning Process Protein Isoforms Proteomics Publishing Recombinants Research Project Grants Role Savings Serum Severities Signal Transduction Symptoms Therapeutic Therapeutic Agents Tissues United States acetaminophen overdose 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.

项目概要该提案的目标是确定几丁质酶 3-like-1 (Chi3l1) 在肝血小板积累中的作用在对乙酰氨基酚 (APAP) 诱导的肝损伤 (AILI) 期间，并评估靶向 Chi3l1 的潜力 AILI 的治疗。 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。既往研究表明，肝血小板聚集和肝内凝血在AILI的加重中发挥着重要作用。我们最近的数据研究表明，在过量服用 APAP 后，小鼠和人类的肝脏中 Chi3l1 的表达上调。 Chi3l1-/- 小鼠出现了减弱的 AILI 和肝内凝血，没有明显的血小板积聚，这是与WT小鼠形成鲜明对比。我们将 CD44 鉴定为 Chi3l1 的受体，并发现在所有 CD44- 在肝脏表达细胞中，Chi3l1/CD44相互作用仅发生在Kupffer细胞上，发挥了关键作用在血小板聚集中。这些发现导致我们假设 Chi3l1 通过 CD44 发出信号库普弗细胞在 APAP 诱导的肝血小板聚集和肝损伤中起关键作用 Chi3l1可能作为治疗AILI的治疗靶点。我们提出三个具体目标 (1) 研究 CD44 在介导 AILI 中 Chi3l1 病理效应中的关键作用，(2) 阐明 Chi3l1/CD44轴介导Kupffer细胞诱导的肝血小板聚集的机制，（3）靶点 Chi3l1 用于治疗 AILI。