Role of synovial lining fibroblasts in inflammatory arthritis

滑膜内层成纤维细胞在炎症性关节炎中的作用

基本信息

批准号：
10453199
负责人：
Pallavi Bhattaram
金额：
$ 20.66万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10453199
关键词：
ATAC-seq Adolescent Alleles Apoptosis Apoptotic Arthritis Autoimmune Automobile Driving Biological Biological Assay Cartilage Cell Survival Cells Characteristics Chromatin Chronic Chronic Childhood Arthritis Chronic Disease Clinical Data Degenerative polyarthritis Development Disease Disease remission Doxycycline Epigenetic Process Exhibits Failure Fibroblasts Flow Cytometry Fluorescence Fluorescence Microscopy Frozen Sections Gene Expression Genes Goals Homeostasis Human Inflammation Inflammatory Inflammatory Arthritis Joint Capsule Joints Label Life Malignant Neoplasms Memory Molecular Multipotent Stem Cells Mus Pathogenesis Pathologic Pathology Patients Pharmaceutical Preparations Phase Play Proliferating Property Psoriatic Arthritis Publications Publishing Recurrence Relapse Reporting Repression Research Resistance Resolution Rheumatoid Arthritis Role SOX11 gene SOX4 gene Surface Symptoms Synovial Membrane TNF gene Testing Time Tissues Transgenic Mice Transplantation arthropathies articular cartilage base cancer stem cell cell type daughter cell disease phenotype epigenetic memory experimental study health related quality of life in vivo inflammatory milieu insight joint destruction joint inflammation novel prevent single-cell RNA sequencing stem-like cell subchondral bone therapy resistant transcriptome sequencing transcriptomics

项目摘要

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.

项目概要成纤维细胞样滑膜细胞（FLS）是关节表面的细胞。它们在病理学中发挥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类癌细胞，逃避凋亡、增殖并产生降解关节的分解代谢因子软骨和软骨下骨。一旦发生转变，FLS 就会在以下环境中保留其攻击性特性：尽管将它们从炎症微环境中去除。表观遗传重塑被认为是根本原因。在本提案中，我们将重点关注位于滑膜内层的 FLS 的特定亚型（L-FLS）。我们的首要假设是 L-FLS 发挥疾病引发干细胞样细胞的作用。我们建议他们通过引发其他攻击性FLS而成为关节退化的始作俑者和延续者亚人群并通过获得与缓解失败有关的长期表观遗传记忆。我们将通过确定 L-FLS 是否具有特征（例如分化为另一种特征）来检验这一假设。攻击性亚群，即使在炎症消退后仍保留其表观遗传变化。在目标 1 中，我们将使用谱系追踪来识别 L-FLS 可以引起其他病理亚型。在目标 2 下，我们将研究 L-FLS 的内在表观遗传是否不可逆转并导致疾病持续存在。成功的该提案的完成将使 L-FLS 成为 IJD 驱动细胞，具有启动分解代谢的能力关节的变化以及导致疾病表型的持续存在。我们预计 L-FLS 将被确定为预防治疗耐药和症状复发的理想目标。