Role of synovial lining fibroblasts in inflammatory arthritis

项目摘要 成纤维样滑膜细胞(FLS)是关节表面衬里的细胞。它们在病理学中起着关键作用。 炎症性关节疾病(IJD)，如类风湿性关节炎、牛皮癣关节炎和青少年特发性 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 肿瘤样细胞，逃避细胞凋亡，增殖，产生分解代谢因子，使关节退化。 软骨和软骨下骨。一旦被改造，FL就会保留它们的侵略性 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。在这项建议中，我们将重点放在滑膜衬里中的一种特殊的FLS亚型上。 (L-自由女神队)。我们的主要假设是，L-FLS作为致病干细胞发挥作用。我们建议 它们作为关节退行性变的始发者和永久者，通过产生其他侵袭性的前交叉韧带 并通过获得与缓解失败有关的长期表观遗传记忆。我们会 通过确定L-FLS是否具有分化为另一种类型的特征来检验这一假设 侵袭性亚群，并保留其表观遗传学的变化，即使在炎症消退。在目标1中，我们 将L家系追踪鉴定为FLS可引起其他病理亚型。在目标2下，我们将 研究L-FLS的内在表观遗传是否是不可逆转的，是否与疾病的持久性有关。成功 这项提议的完成将建立L-FLS作为IJD驱动细胞，具有启动分解代谢的能力 关节的变化以及疾病表型的持久性。我们预计，L-FLS将是 被确定为预防治疗耐药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.