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：
8954302
负责人：
Xiaosong Joy Jiang
金额：
$ 7.82万
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 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8954302
关键词：
Adaptor Signaling Protein Address Affect Attenuated Binding Biological Response Modifiers C-terminal CD4 Positive T Lymphocytes Carbohydrates Caspase-1 Cell physiology Cholestasis Citrus Coculture Techniques Data Development Disease Event Fibrosis Future Galactosides Galectin 3 Head Helper-Inducer T-Lymphocyte Hepatic Hepatic Fibrogenesis Human Immune Immunoprecipitation Inflammation Inflammatory Injury 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 fibrogenesis in vivo inhibitor/antagonist interleukin-12 subunit p35 interleukin-23 liver injury macrophage mortality novel therapeutics paracrine public health relevance receptor stellate cell transdifferentiation vector

Adaptor Signaling Protein Address Affect Attenuated Binding Biological Response Modifiers C-terminal CD4 Positive T Lymphocytes Carbohydrates Caspase-1 Cell physiology Cholestasis Citrus Coculture Techniques Data Development Disease Event Fibrosis Future Galactosides Galectin 3 Head Helper-Inducer T-Lymphocyte Hepatic Hepatic Fibrogenesis Human Immune Immunoprecipitation Inflammation Inflammatory Injury 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 fibrogenesis in vivo inhibitor/antagonist interleukin-12 subunit p35 interleukin-23 liver injury macrophage mortality novel therapeutics paracrine public health relevance receptor stellate cell transdifferentiation vector

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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（由适用提供）：原发性胆汁肝硬化（PBC）是发病率和死亡率的主要原因。 PBC的发病机理在很大程度上未知。但是，T细胞功能的失调被认为起着重要作用。新兴的证据表明，不仅T细胞，先天免疫反应和促炎巨噬细胞在PBC发病机理中也起着重要作用。 Galectin-3（GAL3），已知ß-半乳糖苷结合讲座可以调节巨噬细胞激活和T细胞功能。 GAL3还调节肝纤维发生。我们的初步数据表明，人和鼠PBC的生命中GAL3和炎性体信号传导上调。 GAL3和炎性组成分NLRP3在PBC患者的肝脏中共定位。因此，我们假设Galectin-3控制巨噬细胞中炎性体信号传导的激活，并控制巨噬细胞和T辅助细胞的IL-17产生，从而导致PBC中的进行性感染和纤维化。为了检验这一假设，我们的具体目的是1）确定GAL3是否在PBC中调节NLRP3炎性体激活和IL-17的产生； 2）研究GAL3是否介导了巨噬细胞的IL-17产生，而PBC中的Th17; 3）确定在PBC中是否保护了GAL3的缺失。此外，我们将在PBC鼠模型中使用GAL3抑制剂改性果果蛋白（MCP）来评估其治疗效果。这些研究可能导致针对PBC的新治疗方式发展。