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Galectin-3 in Primary biliary Cirrhosis

Galectin-3 在原发性胆汁性肝硬化中的作用

基本信息

批准号：
9070672
负责人：
Xiaosong Joy Jiang
金额：
$ 7.85万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-06-01 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9070672
关键词：
Adaptor Signaling Protein Address Affect Attenuated Binding Biological Response Modifiers C-terminal CASP1 gene CD4 Positive T Lymphocytes Carbohydrates Cell physiology Cholestasis Citrus Coculture Techniques Data Development Disease Event Fibrosis Future Galactosides Galectin 3 Head Health Helper-Inducer T-Lymphocyte Hepatic Hepatic Fibrogenesis Human Immune Immunoprecipitation Inflammation Inflammatory Injury Interleukin-1 beta Interleukin-17 Intrahepatic bile duct Lead Lectin Liver Liver Failure Macrophage Activation Mass Spectrum Analysis Mediating Mediator of activation protein Modality Modeling Morbidity - disease rate Mus Mutation N-terminal Pathogenesis Pathway interactions Patients Pectins Phenotype Play Primary biliary cirrhosis Production Proteomics Reaction Regulation Role Signal Transduction T-Lymphocyte Tail Testing Therapeutic Effect Transcription Factor AP-1 Ursodeoxycholic Acid autocrine base bile acid transporter curative treatments fibrogenesis in vivo inhibitor/antagonist interleukin-23 liver injury macrophage mortality mouse model novel therapeutic intervention novel therapeutics paracrine receptor stellate cell transdifferentiation vector

项目摘要

DESCRIPTION (provided by applicant): Primary biliary cirrhosis (PBC) is a major cause of morbidity and mortality. The pathogenesis of PBC is largely unknown. Dysregulation of T cell functions is thought to play an important role however; emerging evidence has shown that not only T cells, innate immune reactions and proinflammatory macrophages also play important roles in PBC pathogenesis. Galectin-3 (gal3), a ß-galactoside-binding lectin is known to regulate macrophage activation and T cell functions; and gal3 also modulates liver fibrogenesis. Our preliminary data have shown that gal3 and inflammasome signaling were upregulated in human and murine PBC livers; gal3 and the inflammasome component NLRP3 were colocalized in the liver from PBC patients. Therefore, we hypothesize that galectin-3 controls the activation of inflammasome signaling in macrophages and the consequent IL-17 production by macrophages and T helper cells, leading to progressive inflammation and fibrosis in PBC. To test this hypothesis, our SPECIFIC AIMS are 1) To determine if gal3 modulates NLRP3 inflammasome activation and IL-17 production in PBC; 2) To study if gal3 mediates IL-17 production by macrophages and Th17 in PBC; 3) To determine if the deletion of gal3 is protective in PBC. In addition, we will use the Gal3 inhibitor modified citrus pectin (MCP) in the PBC murine model to assess its therapeutic effect. These studies may lead to the development of new therapeutic modalities against PBC.

描述(申请人提供)：原发性胆汁性肝硬变(PBC)是发病率和死亡率的主要原因。PBC的发病机制在很大程度上尚不清楚。然而，T细胞功能失调被认为起着重要作用；新的证据表明，不仅T细胞、先天免疫反应和促炎性巨噬细胞在PBC的发病机制中也起着重要作用。Galectin-3(Gal3)是一种与半乳糖苷结合的凝集素，可调节巨噬细胞激活和T细胞功能；Gal3还调节肝纤维化。我们的初步数据显示，Gal3和炎症体信号在人和小鼠的PBC肝脏中上调；Gal3和炎症体成分NLRP3在PBC患者的肝脏中共存。因此，我们推测Galectin-3控制巨噬细胞炎症小体信号的激活以及随后巨噬细胞和辅助性T细胞产生IL-17，从而导致PBC的进行性炎症和纤维化。为了验证这一假说，我们的具体目标是1)确定Gal3是否调节PBC中NLRP3炎症体的激活和IL-17的产生；2)研究Gal3是否介导巨噬细胞产生IL-17和PBC中Th17的产生；3)确定Gal3的缺失是否对PBC具有保护作用。此外，我们还将在PBC小鼠模型中使用Gal3抑制剂修饰的柑橘果胶(MCP)来评估其治疗效果。这些研究可能会导致针对PBC的新治疗方法的开发。