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.

项目总结/摘要 在理解不同类型的滑膜成纤维细胞如何促进 类风湿性关节炎（RA）病理，限制阻断成纤维细胞介导的关节炎症的能力， 软骨糜烂推动这项提案的长期目标是确定专门针对成纤维细胞的方法 在炎症性关节炎中的作用。本提案的目的是研究血小板衍生生长因子 PDGFRs作为这些靶点之一。尽管PDGFRs是成纤维细胞的有效刺激物， 在炎症性关节炎的PDGFR研究中， 已经落后于其他疾病领域。这项研究的基本原理是，它将推动新的治疗方法， 自身免疫性炎症性关节炎的方法，通过开发临床前数据来支持关节炎 新开发的抗PDGFR疗法的适应症，并通过发现新的成纤维细胞途径， 未来的临床目标形成这一提议的中心假设是PDGFRα和PDGFRβ 独立地促进炎性关节炎和成纤维细胞介导的关节病理学的发展。 该假设建立在初步数据基础上，初步数据显示PDGFRα或 RA滑膜成纤维细胞中的PDGFRβ激活，并证明不同的成纤维细胞亚群可以被激活。 基于PDGFRα和PDGFRβ表达直接从滑膜分离。这一假设将得到检验 有三个具体目标：（1）确定PDGFRα和PDGFRβ表达如何调节炎症性关节炎 （2）确定滑膜成纤维细胞中PDGFRα和PDGFRβ的活化是如何调节的;以及（3） 在临床前炎性关节炎模型中测试抗PDGFR治疗组合。Aim 1使用诱导型 PDGFRs的遗传缺失以测试其在小鼠模型中关节炎发展中的功能并与其相关 PDGFR表达的成纤维细胞群的转录谱的功能，这些成纤维细胞群直接从 滑膜目的2：分离滑膜成纤维细胞中PDGFRα和PDGFRβ激活的差异效应， 检测基因表达、膜相互作用和配体可用性。目的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治疗， 与其他类型的疗法相结合。申请人认为，这种方法是创新的，因为它 通过将为其他疾病开发的遗传工具与新的流动相结合， 细胞计数和生物信息学方法来分析体外和直接离体的成纤维细胞功能。的 提出的研究是重要的，因为确定PDGFRα和PDGFRβ的表达和信号传导 调节成纤维细胞和滑膜生物学，预计将评估新的PDGF特异性药物如何用于 治疗RA，并增加我们对不同滑膜成纤维细胞群 有助于炎症性关节炎的发病机制。