Elucidation of mechanisms governing the activities of synovial fibroblasts

项目摘要 成纤维细胞样滑膜细胞填充关节的滑膜表面。他们在这方面发挥着关键作用， 维持关节健康和关节炎疾病的病理学。我们的数据表明，SOXC 一组转录因子是实现成纤维细胞病理特性的关键因素， 就像滑膜细胞一样SOXC蛋白以前被证明是间充质细胞存活的关键。 和神经祖细胞，在胚胎中产生多种身体结构，包括 骨骼心脏和神经系统它们还被证明可以促进细胞的增殖、迁移和 许多类型的癌细胞的侵袭性。我们的初步结果表明，SoxC基因 有助于关节炎疾病中成纤维细胞样滑膜细胞的侵袭性癌细胞样行为。 该项目的首要假设是，SOXC蛋白在细胞中的生物活性与其在细胞中的表达有关。 成纤维细胞样滑膜细胞显著促进炎症介导的滑膜变性， 关节炎和相关关节疾病中的关节软骨和骨。我们的首要目标是确定 SoxC基因是否参与调控基因表达和细胞行为， 成纤维细胞样滑膜细胞，处于炎症应激下。然后我们将调查 上游分子机制，调节SOXC蛋白的活性，在成纤维细胞样 滑膜细胞接下来，我们将测试阻断SOXC蛋白是否在成纤维细胞样滑膜细胞中发挥作用 减少关节炎疾病中的关节退化。我们预计，我们的新发现将导致更多的 对关节病理中成纤维细胞样滑膜细胞的分子调控有深刻的理解。 这些新的发现可能会影响新的，成功的滑膜成纤维细胞策略的设计， 骨关节炎和类风湿性关节炎患者的关节修复和再生疗法 关节炎

PROJECT SUMMARY Fibroblast-like synoviocytes populate the synovial surfaces of the joints. They have critical roles in the maintenance of joint health and in the pathology of arthritic diseases. Our data suggest that the SOXC group of transcription factors are key players in implementing the pathological properties of fibroblast- like synoviocytes. SOXC proteins were previously shown to be critical for the survival of mesenchymal and neural progenitor cells that give rise in the embryo to multiple body structures, including the skeleton, heart, and nervous system. They were also shown to promote the proliferation, migration and invasive properties of many types of cancer cells. Our preliminary results suggest that SoxC genes contribute to the aggressive cancer cell-like behavior of fibroblast-like synoviocytes in arthritic diseases. The overarching hypothesis of this project is that the biological activities of SOXC proteins in the fibroblast-like synoviocytes significantly contribute to the inflammation-mediated degeneration of articular cartilage and bones in arthritis and related joint diseases. Our primary goal is to determine whether the SoxC genes are involved in regulation of gene expression and cellular behavior of fibroblast-like synoviocytes that are under the stress of inflammation. We will then investigate the upstream molecular mechanisms that regulate the activities of SOXC proteins in fibroblast-like synoviocytes. Next, we will test whether blocking SOXC protein functions in fibroblast-like synoviocytes reduces joint degeneration in arthritic diseases. We anticipate that our new findings will lead to a more profound understanding of the molecular regulation of fibroblast-like synoviocytes in joint pathologies. These new findings will likely impact the design of new, successful strategies for synovial fibroblast- based joint repair and regeneration therapies for patients suffering from osteoarthritis and rheumatoid arthritis.