Functional Antagonists of EBI12/GPR183 as chemical probes for inflammation

描述（由申请人提供）：微环境特异性对淋巴组织内B淋巴细胞分化的影响越来越受到重视。该领域的一个令人兴奋的新进展是揭示了一个新的趋化轴，涉及孤儿g蛋白偶联受体（GPCR）， Epstein- Barr病毒诱导基因2 （EBI2）对氧甾醇化合物的识别。EBI2 （Epstein-Barr病毒诱导基因2）是一种在B细胞上表达的g蛋白偶联受体（GPCR），激活后高度诱导。最近的基因靶向实验显示，EBI2-/- B细胞表现出迁移缺陷，导致T细胞依赖性抗体反应严重受损。最近，两个研究小组做出了一个不太可能的发现，即以前已知与核受体结合的羟甾醇化合物是EBI2的生理配体。本应用程序旨在开发工具，以探索体内生物学和治疗潜力的这一令人兴奋的免疫细胞趋化性的新成分。拟议的工作将MLPCN用于筛选EBI2的小分子抑制剂，这些抑制剂可以在体内抑制抗体的产生，并且可能对炎症有更广泛的影响。展望未来，这些探针可用于自身抗体依赖性炎症疾病（如类风湿关节炎和狼疮）的小鼠模型，或更广泛地应用于检查对全身炎症的影响。

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.