Functional Antagonists of EBI12/GPR183 as chemical probes for inflammation

描述(由申请人提供)：越来越多的人认识到微环境对淋巴组织内B淋巴细胞分化的特定影响。该领域一个令人兴奋的新进展是揭示了一个新的趋化轴，它涉及到孤儿G蛋白偶联受体(GPCR)--Epstein-Barr病毒诱导基因2(EBI2)对氧固醇化合物的识别。EBI2(Epstein-Barr病毒诱导基因2)是一种表达于B细胞的G蛋白偶联受体，激活后高度诱导表达。最近的基因打靶实验表明，EBI2-/-B细胞表现出缺陷的迁移，导致T细胞依赖的抗体反应严重受损。最近，两个研究小组做出了一个不太可能的发现，即以前已知的与核受体结合的氧固醇化合物是EBI2的生理配体。这项应用寻求开发工具，以探索体内生物学和治疗潜力的这种令人兴奋的新成分的免疫细胞趋化。这项拟议的工作利用MLPCN来筛选EBI2的小分子抑制剂，这些小分子抑制剂可以在体内发挥作用，钝化抗体的产生，也许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型炎症性疾病的小鼠模型，如类风湿性关节炎和狼疮，或更广泛地应用于检测对全身炎症的影响。

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.