Role of synovial lining fibroblasts in inflammatory arthritis

项目摘要 成纤维细胞样滑膜细胞（FLS）是关节表面的衬里细胞。它们在病理学上起着关键作用 炎症性关节疾病（IJD），如类风湿性关节炎，银屑病关节炎和青少年特发性关节炎 关节炎在慢性炎症下，FLS经历表观遗传重塑，并转化为侵袭性的， 癌样细胞逃避凋亡，增殖，并产生分解代谢因子，降解关节炎。 软骨和软骨下骨。一旦转化，已知FLS在体内保留其攻击性特性， 尽管将它们从炎症微环境中移除。表观遗传重塑被认为是 根本原因在这个建议中，我们将重点放在一个特定的亚型FLS是位于滑膜衬里 （L-FLS）。我们的首要假设是L-FLS作为疾病启动干细胞样细胞发挥功能。我们提出 它们通过引起其他侵袭性FLS而作为关节退行性变的始动者和永久者 亚群，并通过获得长期的表观遗传记忆，这是牵连到未能缓解。我们将 通过确定L-FLS是否具有特征来检验这一假设，例如，分化成另一种 侵袭性亚群，甚至在炎症消退后仍保留其表观遗传变化。在目标1中， 将使用谱系追踪来确定L-FLS可以引起其他病理亚型。根据目标2，我们将 研究L-FLS内在表观遗传是否是不可逆的并导致疾病持续存在。成功 完成这一建议将建立L-FLS作为IJD驱动细胞，它具有启动分解代谢的能力 关节中的变化以及赋予疾病表型的持续性。我们预计L-FLS将是 被确定为防止治疗耐药性和症状复发的理想靶点。

Project Summary Fibroblast-like synoviocytes (FLS) are cells, lining of the joint surfaces. They play a critical role in the pathology of Inflammatory Joint Diseases (IJD), such as rheumatoid arthritis, psoriatic arthritis and juvenile idiopathic arthritis. Under chronic inflammation, FLS undergo epigenetic remodeling and are transformed into aggressive cancer-like cells, which evade apoptosis, proliferate, and produce catabolic factors that degrade the articular cartilage and subchondral bone. Once, transformed, the FLS are known to retain their aggressive properties in spite of removing them from the inflammatory microenvironment. Epigenetic remodeling is suggested as the underlying cause. In this proposal, we will focus on a specific subtype of FLS that are located in synovial lining (L-FLS). Our overarching hypothesis is that the L-FLS function as disease-initiating stem-like cells. We propose that they act as the initiators and perpetuators of joint degeneration by giving rise to other aggressive FLS subpopulations and by acquiring long-term epigenetic memory that is implicated in failure to remission. We will test this hypothesis by determining if the L-FLS possess characteristics, such as, differentiation into another aggressive subpopulation and retain their epigenetic changes even after resolution of inflammation. In Aim 1 we will use lineage tracing to identify the L-FLS can give rise to other pathological subtypes. Under Aim 2 we will investigate if intrinsic epigenetic in L-FLS are irreversible and are responsible for disease persistence. Successful completion of this proposal will establish L-FLS as IJD-driving cells, which possess the ability to initiate catabolic changes in the joint as well as confer persistence of the disease phenotype. We anticipate that the L-FLS will be identified as ideal targets to prevent therapeutic resistance and recurrence of symptoms.