Investigating how platelet-derived growth factor receptors direct synovialfibroblast-mediated pathology in inflammatory arthritis

研究血小板衍生生长因子受体如何指导炎症关节炎中滑膜成纤维细胞介导的病理学

• 批准号: 10247966
• 负责人: Jan Christian Lood
• 金额: $ 38.83万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-10 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10247966
• 关键词: Antibodies; Arthritis; Atherosclerosis; Autoimmune Process; Automobile Driving; Bioinformatics; Biology; Cartilage; Cell physiology; Cells; Clinical; Clinical Trials; Custom; Data; Development; Disease; Disease remission; Drug Combinations; Eye diseases; Fc Receptor; Fibroblasts; Fibrosis; Flow Cytometry; Future; Gene Expression; Genetic; Genetic Transcription; Goals; Health; Heterodimerization; Homo; Human; Hyperplasia; Immunosuppression; In Vitro; Inflammation; Inflammatory; Inflammatory Arthritis; Joints; Knowledge; Ligands; Malignant Neoplasms; Mediating; Membrane; Methods; Mission; Modeling; Monoclonal Antibodies; Morphology; Mus; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Phenotype; Platelet-Derived Growth Factor; Platelet-Derived Growth Factor Receptor; Platelet-Derived Growth Factor alpha Receptor; Population; Public Health; Receptor Activation; Receptor Signaling; Research; Rheumatoid Arthritis; Risk; Serum; Shapes; Signal Transduction; Stimulus; Stromelysin 1; Surface; Synovial Cell; Synovial Membrane; TNF gene; Testing; Therapeutic; Tissues; United States National Institutes of Health; aptamer; autoimmune arthritis; base; bone erosion; cadherin-11; cell type; functional outcomes; improved; in vitro Assay; infection risk; innovation; joint inflammation; migration; mouse model; nano-string; novel; novel therapeutic intervention; novel therapeutics; platelet-derived growth factor BB; pre-clinical; prevent; receptor; receptor expression; therapeutic development; tool; transcriptome sequencing; treatment response

PROJECT SUMMARY/ABSTRACT There is a fundamental gap in understanding of how different types of synovial fibroblasts contribute to rheumatoid arthritis (RA) pathology, restricting the ability to block fibroblast-mediated joint inflammation and cartilage erosions. The long-term goal driving this proposal is to identify ways to specifically target fibroblast function in inflammatory arthritis. The objective of this proposal to investigate platelet-derived growth factor receptors (PDGFRs) as one of these targets. Although PDGFRs are potent stimulators of fibroblast proliferation and migration and are known to be upregulated in RA, PDGFR research in inflammatory arthritis has lagged behind other disease fields. The rationale for this study is that it will advance new therapeutic approaches in autoimmune inflammatory arthritis by both developing preclinical data to support an arthritis indication for newly developed anti-PDGFR therapeutics and by discovering novel fibroblast pathways for future clinical targeting. The central hypothesis shaping this proposal is that that PDGFRα and PDGFRβ independently contribute to the development of inflammatory arthritis and fibroblast-mediated joint pathology. This hypothesis is built on preliminary data showing different functional outcomes following PDGFRα or PDGFRβ activation in RA synovial fibroblasts and demonstrating that different fibroblast subpopulations can be isolated directly from the synovium based on PDGFRα and PDGFRβ expression. This hypothesis will be tested in three specific aims: (1) Determine how PDGFRα and PDGFRβ expression regulates inflammatory arthritis development; (2) Determine how PDGFRα and PDGFRβ activation is regulated in synovial fibroblasts; and (3) Test anti-PDGFR treatment combinations in a preclinical inflammatory arthritis model. Aim 1 uses inducible genetic deletion of PDGFRs to test their function in arthritis development in a mouse model and correlates this function with the transcriptional profiles of PDGFR-expressing fibroblast populations isolated directly from the synovium. Aim 2 isolates differential effects of PDGFRα and PDGFRβ activation in synovial fibroblasts by examining gene expression, membrane interactions, and ligand availability. Aim 3 uses the preclinical serum transfer mouse arthritis model to test how anti-PDGFR antibodies may augment arthritis treatment when combined with other types of therapies. This approach is innovative, in the applicant's opinion, because it reenergizes PDGFR research in RA by combining genetic tools developed for other diseases with new flow cytometric and bioinformatic methods to analyze fibroblast function both in vitro and directly ex vivo. The proposed research is significant because determining how PDGFRα and PDGFRβ expression and signaling regulates fibroblast and synovial biology is expected to assess how new PDGF-specific drugs can be used to treat RA and to increase our fundamental understanding of how different synovial fibroblast populations contribute to inflammatory arthritis pathogenesis.

项目摘要/摘要 在理解不同类型的滑膜成纤维细胞如何参与 类风湿关节炎(RA)病理，限制阻止成纤维细胞介导的关节炎症和 软骨侵蚀。推动这一提议的长期目标是找出专门针对成纤维细胞的方法 在炎症性关节炎中的作用。这项建议的目的是研究血小板衍生生长因子 受体(PDGFRs)作为这些靶点之一。尽管PDGFRs是成纤维细胞的有效刺激因子 已知在炎症性关节炎的RA、PDGFR研究中上调了增殖和迁移 已经落后于其他疾病领域。这项研究基本原理是它将推动新的治疗方法 通过开发临床前数据来支持关节炎的自身免疫性炎性关节炎的方法 新开发的抗PDGFR治疗药物的适应症和发现新的成纤维细胞途径 未来的临床靶向。形成这一提议的中心假设是，PDGFRα和PDGFRβ 独立促进炎性关节炎和成纤维细胞介导的关节病理的发展。 这一假说建立在初步数据的基础上，这些数据显示了α或PDGFR术后不同的功能结果。 PDGFRβ在RA滑膜成纤维细胞中的激活以及不同的成纤维细胞亚群可以 直接从滑膜中分离出PDGFRα和PDGFFRβ表达。这一假设将得到检验。 有三个具体目的：(1)确定PDGFRα和PDGFFRβ的表达如何调节炎性关节炎 (2)确定PDGFRα和PDGFFRβ在滑膜成纤维细胞中的激活是如何调节的；以及(3) 在临床前炎症性关节炎模型中测试抗PDGFR治疗组合。目标1使用诱导式 在小鼠模型中检测PDGFRs的基因缺失以测试其在关节炎发展中的功能并将其关联起来 直接分离的PDGFR表达成纤维细胞群体的转录谱功能 滑膜。目的2不同分离株对滑膜成纤维细胞中PDGFRα和PDGFFRβ活化的差异 检测基因表达、膜相互作用和配基的可用性。目标3使用临床前血清 转移小鼠关节炎模型以测试抗PDGFR抗体如何增强关节炎的治疗 与其他类型的治疗相结合。申请人认为，这种方法是创新的，因为它 通过将针对其他疾病开发的基因工具与新流程相结合，为RA的PDGFR研究注入新的活力 用细胞计量学和生物信息学方法分析成纤维细胞的体外和直接体外功能。这个 拟议的研究具有重要意义，因为确定PDGFRα和PDGFRβ的表达和信号转导 调节成纤维细胞和滑膜生物学有望评估新的PDGF特异性药物如何用于 治疗类风湿关节炎并增加我们对不同滑膜成纤维细胞如何 参与炎症性关节炎的发病机制。