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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.

项目总结成纤维细胞样滑膜细胞分布在关节的滑膜表面。他们在这一过程中扮演着关键角色维持关节健康和关节炎疾病的病理学。我们的数据表明SOXC 一组转录因子在实现成纤维细胞的病理特性方面起着关键作用- 就像滑膜细胞一样。SOXC蛋白先前被证明对间充质细胞的生存至关重要以及在胚胎中产生多种身体结构的神经前体细胞，包括骨骼、心脏和神经系统。研究还表明，它们还能促进生物的扩散、迁移和多种癌细胞的侵袭性。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。该项目的主要假设是SOXC蛋白在细胞内的生物活性成纤维细胞样滑膜细胞在炎症介导的滑膜变性中起重要作用关节软骨和骨骼在关节炎及相关关节疾病中的作用。我们的首要目标是确定 SoxC基因是否参与了基因表达和细胞行为的调控炎症压力下的成纤维细胞样滑膜细胞。然后我们将调查调控成纤维细胞样中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蛋白在成纤维细胞样滑膜细胞中的功能减少关节炎疾病中的关节退行性变。我们预计，我们的新发现将导致更多对成纤维样滑膜细胞在关节病理中的分子调控有深刻的认识。这些新的发现可能会影响滑膜成纤维细胞新的、成功的策略的设计。骨性关节炎和类风湿患者的基础关节修复和再生治疗关节炎。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

MyD88 dimerization inhibitor ST2825 targets the aggressiveness of synovial fibroblasts in rheumatoid arthritis patients.

DOI：
10.1186/s13075-023-03145-0
发表时间：
2023-09-25
期刊：
Arthritis research & therapy
影响因子：
4.9
作者：
通讯作者：

Chronic exposure to TNF reprograms cell signaling pathways in fibroblast-like synoviocytes by establishing long-term inflammatory memory.

长期接触TNF通过建立长期的炎症记忆来重新编程成纤维细胞样的滑膜细胞中的细胞信号通路。

DOI：
10.1038/s41598-020-77380-9
发表时间：
2020-11-20
期刊：
Scientific reports
影响因子：
4.6
作者：
Gangishetti U;Ramirez-Perez S;Jones K;Arif A;Drissi H;Bhattaram P
通讯作者：
Bhattaram P

Targeting MyD88 Downregulates Inflammatory Mediators and Pathogenic Processes in PBMC From DMARDs-Naïve Rheumatoid Arthritis Patients.

针对MyD88的MyD8下调了炎症介质和DMARDS未经类风湿关节炎患者的PBMC的致病过程。

DOI：
10.3389/fphar.2021.800220
发表时间：
2021
期刊：
Frontiers in pharmacology
影响因子：
5.6
作者：
Ramirez-Perez S;Oregon-Romero E;Reyes-Perez IV;Bhattaram P
通讯作者：
Bhattaram P

Targeting inflammasome-dependent mechanisms as an emerging pharmacological approach for osteoarthritis therapy.

DOI：
10.1016/j.isci.2022.105548
发表时间：
2022-12-22
期刊：
ISCIENCE
影响因子：
5.8
作者：
Ramirez-Perez, Sergio;Viridiana Reyes-Perez, Itzel;Emilia Martinez-Fernandez, Diana;Alexis Hernandez-Palma, Luis;Bhattaram, Pallavi
通讯作者：
Bhattaram, Pallavi

Human Adult Fibroblast-like Synoviocytes and Articular Chondrocytes Exhibit Prominent Overlap in Their Transcriptomic Signatures.

DOI：
10.1002/acr2.11255
发表时间：
2021-06
期刊：
ACR open rheumatology
影响因子：
3.4
作者：
Jones K;Angelozzi M;Gangishetti U;Haseeb A;de Charleroy C;Lefebvre V;Bhattaram P
通讯作者：
Bhattaram P