权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Mechanistically based therapeutic strategies in murine primary biliary cholangitis

小鼠原发性胆汁性胆管炎的机制治疗策略

基本信息

批准号：
10337052
负责人：
MERRILL E GERSHWIN
金额：
$ 39.74万
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：
2020
资助国家：
美国
起止时间：
2020-02-10 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10337052
关键词：
3&apos Untranslated Regions Acetates Address Amylose Animal Model Antibodies Autoantigens Autoimmune Autoimmune Diseases Autoimmune Process Autoimmunity B-Lymphocytes Bile Acids Biology Butyrates CCR6 gene CXCR3 gene Cell Compartmentation Cells Cholangitis Coin Collaborations Colon Complement Data Defect Development Diabetes Mellitus Diet Disease Elements Enzymes Epigenetic Process Excision Female Fibrosis Future Genes Goals Hepatology Histones Human Immune Immune Tolerance Immunology Inbred NOD Mice Individual Inflammation Interferon Receptor Interferon Type I Interferons Interleukin-12 Lead Link Liver Liver diseases Maize Mediating Modeling Molecular Biology Monoclonal Antibodies Mus Natural History Paper Pathogenicity Pathology Pathway Analysis Pathway interactions Persons Pilot Projects Play Portal vein structure Prevention Primary biliary cirrhosis Pruritus Publishing Receptor Signaling Refractory Regulation Regulatory T-Lymphocyte Resources Role Severity of illness Sex Bias Signal Pathway Signal Transduction Starch Structure of germinal center of lymph node TLR7 gene Therapeutic United States National Institutes of Health Volatile Fatty Acids Work X Chromosome X Inactivation alternative treatment autoreactive B cell autoreactivity base comparative efficacy dietary editorial experience genome wide association study gut microbiome gut microbiota immunoregulation inhibitor innovation metabolomics molecular pathology multidisciplinary novel strategies prevent restoration small molecule treatment response treatment strategy

项目摘要

Summary The treatment of primary biliary cholangitis (PBC) has lagged behind other autoimmune diseases. We propose to challenge this void with our multidisciplinary team with expertise in metabolomics, immunology, molecular biology and pathology. We submit that our use of ARE–/– mice are a powerful new model as mice recapitulate human PBC with female predominance, AMAs, portal inflammation, increased total bile acids, itching, fibrosis and elevated female expression of type I interferon (IFN), required for TLR7 mediated function. We will first propose an entirely new approach to treat autoimmunity, in which depletion of pathogenic immune cells in combination with gut microbiome metabolite therapy restores tolerance. Autoimmune liver diseases are ideal for such therapies because the liver is situated upstream from the colon. Indeed, if pathogenic cell removal, followed by tolerogenic diets work in PBC (our Aim 1), it should lead to trials in other autoimmune diseases. Th1 or Th17 cell removal is a radical new approach, and it is important to complement this with understanding of individual Th1 or Th17/Tfh/germinal centre pathway molecules, to understand whether Th1 or Th17 biology underpins PBC. We will address pathway involvement by downregulating effector function by modulating TLR7 and altering germinal center function (Aim 2) and/or directly addressing IFN receptor signaling (Aim 3). These goals are based on our data, and unique resources that directly target the mechanisms of autoimmune cholangitis. Our group has a wealth of published/unpublished data including extensive experience in modulating autoimmunity by diet and metabolites. Hence our three goals are firstly to eliminate pathogenic cells through antibody depletion of Th1 (CXCR3 mAb), or Th17 and Tfh (CCR6 mAb), followed by immune restoration/regulation with beneficial bacterial metabolites that boost Tregs and promote tolerance. This step involves use of HAMS (high amylose maize starch) diets that produce very large amounts of gut butyrate or acetate. This approach has worked spectacularly well in our hands for diabetes in the NOD mouse. Our second goal is to modulate TLR7, critical for GC formation, and prevent disease in female ARE–/– mice; TLR7 is highly expressed in female ARE–/– mice. These data may lead to future opportunities using small molecules that target TLR7 signaling. In our third and final aim we propose that inhibition of type I IFN receptor signaling will be therapeutic. We know that deletion of the type I IFN receptor in ARE–/– mice reduces disease severity. Thus, we will block the IFN receptor with a mAb and JAK/STAT signaling with a JAK inhibitor. Collectively we submit that this proposal is innovative, likely to lead to better therapeutic approaches, and has importance not only in PBC but generically in other autoimmune diseases.

总结