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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（由申请人提供）：原发性胆汁性肝硬化（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是未知的。然而，T细胞功能失调被认为起着重要作用;新出现的证据表明，不仅T细胞，先天免疫反应和促炎性巨噬细胞也在PBC发病机制中起着重要作用。半乳糖凝集素-3（gal 3），一种β-半乳糖苷结合凝集素，已知调节巨噬细胞活化和T细胞功能; gal 3还调节肝纤维化。我们的初步数据表明，gal 3和炎症体信号在人类和小鼠PBC肝脏中上调; gal 3和炎症体组分NLRP 3在PBC患者的肝脏中共定位。因此，我们假设半乳糖凝集素-3控制巨噬细胞中炎性体信号传导的激活以及随后巨噬细胞和T辅助细胞产生IL-17，导致PBC中进行性炎症和纤维化。为了验证这一假设，我们的具体目标是1）确定gal 3是否调节PBC中的NLRP 3炎性体活化和IL-17产生; 2）研究gal 3是否介导PBC中巨噬细胞和Th 17的IL-17产生; 3）确定gal 3的缺失是否在PBC中具有保护性。此外，我们将在PBC小鼠模型中使用Gal 3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对PBC的新的治疗方式的发展。