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Functional Antagonists of EBI12/GPR183 as chemical probes for inflammation

EBI12/GPR183 的功能拮抗剂作为炎症化学探针

基本信息

批准号：
8328179
负责人：
ROBERT C RICKERT
金额：
$ 4.88万
依托单位：
SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-03-09 至 2014-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8328179
关键词：
Agonist Animals Anti-Inflammatory Agents Anti-inflammatory Antibodies Antibody Formation Antibody-Producing Cells Antigens Autoantibodies Autoimmune Diseases Autoimmunity B cell differentiation B-Lymphocytes Binding Biological Biological Assay Biology Cell model Cells Cellular biology Chemicals Chemotaxis Cholesterol Clonal Expansion Collaborations Communities Cues Development Disease Drug Delivery Systems Exhibits G-Protein-Coupled Receptors Gene Targeting Genes Genomics Goals Human Human Herpesvirus 4 Immune Immune system Immunobiology Inflammation Inflammatory Lead Life Ligands Lupus Lymphoid Tissue Memory B-Lymphocyte Microbe Mixed Function Oxygenases Modeling Molecular Molecular Probes Mus Nuclear Receptors Pathway interactions Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Phenotype Physiological Process Property Publications Research Rheumatoid Arthritis Role Signal Transduction Specificity Staging Structure-Activity Relationship System T-Lymphocyte Therapeutic Toxin United States National Institutes of Health Work arm base cohort high throughput screening human GPRC5C protein in vivo inhibitor/antagonist migration mouse model novel pre-clinical receptor research study scaffold small molecule small molecule libraries tool vaccine efficacy

项目摘要

DESCRIPTION (provided by applicant): There is a growing appreciation of microenvironment-specific influences on B lymphocyte differentiation within the lymphoid tissue. An exciting new development in the field is the revelation of a novel chemotaxis axis involving the recognition of oxysterol compounds by the orphan G-protein-coupled receptor (GPCR), Epstein- Barr virus-induced gene 2 (EBI2). EBI2 (Epstein-Barr virus-induced gene 2) is a G-protein-coupled receptor (GPCR) expressed on B cells and is highly induced upon activation. Recent gene targeting experiments revealed that EBI2-/- B cells exhibited defective migration, resulting in strongly impaired T cell-dependent antibody responses. Most recently, two research teams made the unlikely discovery that oxysterol compounds, previously known to bind nuclear receptors, are the physiologic ligands for EBI2. This application seeks to develop tools to probe the in vivo biology and therapeutic potential of this exciting new component of immune cell chemotaxis. The proposed work enlists the MLPCN to screen for small molecule inhibitors of EBI2 that can function in vivo to blunt antibody production and, perhaps, have more broad reaching effects on inflammation. Prospectively, these probes could be used in mouse models of autoantibody-dependent inflammatory disease such as rheumatoid arthritis and lupus, or more broadly applied to examine effects on systemic inflammation.

描述（由申请人提供）：人们越来越认识到微环境对淋巴组织内B淋巴细胞分化的特异性影响。该领域令人兴奋的新进展是揭示了一种新的趋化性轴，涉及孤儿G蛋白偶联受体（GPCR），爱泼斯坦-巴尔病毒诱导基因2（EBI 2）对氧固醇化合物的识别。EBI 2（EB病毒诱导基因2）是在B细胞上表达的G蛋白偶联受体（GPCR），并且在活化时高度诱导。最近的基因靶向实验表明，EBI 2-/- B细胞表现出缺陷的迁移，导致强烈受损的T细胞依赖性抗体反应。最近，两个研究小组做出了一个不太可能的发现，即以前已知的结合核受体的氧固醇化合物是EBI 2的生理配体。该申请旨在开发工具来探测免疫细胞趋化性的这种令人兴奋的新组分的体内生物学和治疗潜力。这项拟议的工作将MLPCN用于筛选EBI 2的小分子抑制剂，这些抑制剂可以在体内发挥作用以抑制抗体的产生，并且可能对炎症产生更广泛的影响。因此，这些探针可用于自身抗体依赖性炎症性疾病（如类风湿性关节炎和狼疮）的小鼠模型，或更广泛地应用于检查对全身炎症的影响。