Cellular and Molecular Effectors of Synovitis

描述(申请人提供)：这个协作和协同计划的目标是确定迁入性中性粒细胞和巨噬细胞与常驻滑膜成纤维细胞之间的相互作用如何导致滑膜血管疙瘩的形成和关节破坏。初步结果发现，在K/BxN小鼠关节炎模型中，中性粒细胞和/或巨噬细胞衍生的蛋白/脂类介质和滑膜成纤维细胞黏附分子调节滑膜炎症。移行性炎症细胞产生的可溶性介质被发现以常驻滑膜成纤维细胞为靶点，以重新编程滑膜结构。该计划将确定可溶性介质、其特定表面受体和这些谱系表达的调节蛋白之间的相互作用如何促进滑膜炎症。项目1将确定含有CpG的寡核苷酸与巨噬细胞/树突状细胞中的TLR9之间的相互作用如何触发免疫级联反应，从而诱导干扰素-γ的表达并抑制滑膜炎。项目2将确定中性粒细胞来源的LTB4如何靶向滑膜成纤维细胞以促进滑膜炎。项目3将确定转录后控制机制如何调节调节滑膜炎的中性粒细胞衍生的促炎和抗炎效应分子的产生。项目4将确定钙粘蛋白11，一种调节滑膜组织结构的滑膜成纤维细胞黏附分子，如何在滑膜炎中起作用。关节炎形态核心将提供病理样本的统一形态计量分析，关节炎基因组和生物信息学核心将有助于识别调节滑膜炎症的新基因。该计划中以疾病为重点的机制研究既可以深入了解炎性关节炎的发病机制，也可以确定治疗开发的新靶点。

DESCRIPTION (provided by applicant): The objective of this collaborative and synergistic program is to determine how interactions between immigrant neutrophils and macrophages and resident synovial fibroblasts lead to the formation of synovial pannus and joint destruction. Preliminary results have identified neutrophil and/or macrophage-derived protein/lipid mediators, and a synovial fibroblast adhesion molecule that regulate synovial inflammation in the K/BxN model of murine arthritis. Soluble mediators produced by immigrant inflammatory cells were found to target resident synovial fibroblasts to reprogram the synovial architecture. This program will determine how interactions between soluble mediators, their specific surface receptors, and regulatory proteins expressed by these lineages contribute to synovial inflammation. Project 1 will determine how interactions between CpG-containing oligodeoxyribonucleotides and TLR9 in macrophage/dendritic cells trigger an immune cascade that induces the expression of IFN-gamma and suppresses synovitis. Project 2 will determine how neutrophil-derived LTB4 targets synovial fibroblasts to promote synovitis. Project 3 will determine how post-transcriptional control mechanisms regulate the production of neutrophil-derived pro- and anti-inflammatory effector molecules that regulate synovitis. Project 4 will determine how cadherin 11, a synovial fibroblast adhesion molecule that regulates the architecture of synovial tissue, contributes to synovitis. An arthritis morphology core will provide uniform morphometric analysis of pathological samples and an arthritis genomics and bioinformatics core will facilitate the identification of novel genes that regulate synovial inflammation. The disease-focused mechanistic studies in this program promise both insight into the pathogenesis of inflammatory arthritis and identification of novel targets for therapeutic development.