Elucidation of mechanisms governing the activities of synovial fibroblasts

阐明控制滑膜成纤维细胞活性的机制

基本信息

批准号：
10240650
负责人：
Pallavi Bhattaram
金额：
$ 33.29万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-06 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10240650
关键词：
Adult Affect Age-Years Amino Acids Arthritis Behavior Biochemical Biological Biological Assay Cartilage Cell Surface Proteins Cells Characteristics Chronic Clinical Data Degenerative Disorder Degenerative polyarthritis Disease Embryo Enzymes Exhibits Exposure to Fibroblasts Future Gene Expression Gene Expression Regulation Genes Genetic Transcription Goals Health Heart Immune In Vitro Inflammation Inflammatory Inflammatory Arthritis Joint repair Joints Knee Knowledge Laboratories Lead Maintenance Mass Spectrum Analysis Mediating Mediator of activation protein Mesenchymal Stem Cells Molecular Mus Natural regeneration Nervous system structure Operative Surgical Procedures Pain Pathologic Pathology Pathway interactions Patients Phosphorylation Phosphorylation Site Phosphotransferases Physiology Population Prevention Prevention therapy Property Protein Family Proteins Regulation Replacement Arthroplasty Research Rheumatoid Arthritis Role SOX4 gene Shoulder Signal Pathway Signal Transduction Skeleton Source Stimulus Stress Structure Surface Synovial Cell Synovial Fluid Synovial Membrane Synovitis Testing Therapeutic Intervention Transcript United States arthritis therapy arthropathies articular cartilage base bone cancer cell cancer type cell behavior cell type cytokine design disability human tissue infancy joint destruction joint injury kinase inhibitor migration mimetics mouse model mutant nerve stem cell novel overexpression postnatal prevent progenitor protein function regenerative therapy repaired small hairpin RNA success targeted treatment transcription factor transcriptome

项目摘要

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.

项目概要成纤维细胞样滑膜细胞分布在关节的滑膜表面。他们在其中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参与者像滑膜细胞。 SOXC 蛋白先前被证明对于间充质细胞的存活至关重要以及在胚胎中产生多种身体结构的神经祖细胞，包括骨骼、心脏和神经系统。它们还被证明可以促进扩散、迁移和许多类型癌细胞的侵袭特性。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。该项目的总体假设是 SOXC 蛋白的生物活性成纤维样滑膜细胞显着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骼。我们的首要目标是确定 SoxC 基因是否参与基因表达和细胞行为的调节处于炎症应激下的成纤维细胞样滑膜细胞。然后我们将调查调节成纤维细胞样中 SOXC 蛋白活性的上游分子机制滑膜细胞。接下来，我们将测试阻断SOXC蛋白是否在成纤维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带来更多对关节病理中成纤维样滑膜细胞的分子调节的深刻理解。这些新发现可能会影响滑膜成纤维细胞新的成功策略的设计针对骨关节炎和类风湿患者的基于关节修复和再生的疗法关节炎。