Role of PTPRS in rheumatoid arthritis

PTPRS 在类风湿性关节炎中的作用

• 批准号: 8919240
• 负责人: Nunzio Bottini
• 金额: $ 38.2万
• 依托单位: LA JOLLA INSTITUTE FOR IMMUNOLOGY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8919240
• 关键词: Adhesions; Affect; Affinity; Aggressive behavior; Anti-Tumor Necrosis Factor Therapy; Antirheumatic Agents; Applications Grants; Arthritis; Attention; Behavior; Binding; Cadherins; Cartilage; Cell Line; Cell surface; Cells; Chondroitin Sulfates; Combined Modality Therapy; Data; Disease; Disease remission; Drug Targeting; Equilibrium; Evaluation; Extracellular Domain; Extracellular Matrix; Fibroblasts; Functional disorder; Generations; Goals; Government; Growth; Growth Factor Receptors; Health; Hematopoietic; Heparitin Sulfate; Immunoglobulin Domain; Immunomodulators; Immunosuppression; Immunosuppressive Agents; Inflammation; Inflammatory Response; Invaded; Joints; Laboratories; Light; Mediating; Mediator of activation protein; N-terminal; Names; Neurons; Osteitis; Pathogenesis; Pathway interactions; Patients; Persons; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotyrosine; Physiological; Play; Problem Solving; Protein Tyrosine Kinase; Protein Tyrosine Phosphatase; Proteins; Proteoglycan; Quality of life; Recombinants; Regimen; Regulation; Rheumatoid Arthritis; Role; Safety; Scheme; Severities; Severity of illness; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Stimulus; Treatment Efficacy; Tyrosine; Tyrosine Phosphorylation; Work; axon growth; beta catenin; cell type; cytokine; design; disorder control; extracellular; in vivo; inorganic phosphate; interest; joint destruction; migration; mouse model; neurotransmission; novel; novel strategies; novel therapeutics; therapeutic target

DESCRIPTION (provided by applicant): Fibroblast-like synoviocytes (FLS) are key players in mediating inflammation and joint destruction in rheumatoid arthritis (RA). There is an increased level of attention to this cell type as the possible target of a new generation of anti-RA therapie, which would be used in combination with immunomodulators to help control disease without increasing immune-suppression. The behavior of FLS is controlled by multiple interconnected signal transduction pathways. Several of these pathways involve reversible phosphorylation of proteins on tyrosine residues, which is the result of the balanced action of protein tyrosine kinases (PTKs) and phosphatases (PTPs). PTKs are well-known to be key mediators of FLS growth and invasiveness, and more recently, they are emerging as promising drug targets for RA. On the other hand, almost no work has been done on the PTPs in FLS. This grant application focuses on a transmembrane PTP called PTPRS. PTPRS is expressed at low or undetectable levels in hematopoietic cells but we find it to be highly expressed in FLS. The extracellular domain of PTPRS binds to proteoglycans in the extracellular matrix and binding to different proteoglycans results in differences in the intracellular functions of the phosphatase. This PTPRS-mediated mechanism of regulation of intracellular signaling by the extracellular matrix is called "the proteoglycan switch". We find that the proteoglycan switch regulates in a PTPRS-dependent way the adhesion and invasiveness of FLS. We also find that interfering with the proteoglycan switch in vivo leads to decreased severity of arthritis in a mouse model. Our working hypothesis is that PTPRS is a key regulator of RA FLS destructive behavior. The objectives of this project are to establish PTPRS as a key regulator of extracellular matrix-induced signals in FLS and provide proof of principle that the proteoglycan switch is a drug target for RA. In Aim 1 we will clarify whether PTPRS and the proteoglycan switch affect various aspects of FLS pathophysiology that are relevant to the pathogenesis of RA In Aim 2 we will identify the substrate of PTPRS that is affected by engagement of the proteoglycan switch and look into the signaling pathways controlled by PTPRS in a proteoglycan-dependent way In Aim 3 we will provide proof of principle that targeting PTPRS helps control RA activity in vivo and can be used as a combination therapy with anti-TNF therapy. The results of this project will shed light on the relationship between extracellular matrix composition and intracellular signaling in FLS. The disease-relevant long-term goal is to validate a novel approach to FLS targeted combination therapy of RA.

描述（由申请人提供）：成纤维细胞样的滑膜细胞（FL）是介导类风湿关节炎（RA）炎症和关节破坏的关键参与者。作为新一代抗RA Therapie的可能目标，人们对这种细胞类型的关注程度越来越高，将与免疫调节剂结合使用，以帮助控制疾病而不增加免疫抑制。 FL的行为由多个互连信号转导途径控制。这些途径中有几种涉及蛋白质在酪氨酸残基上的可逆磷酸化，这是蛋白质酪氨酸激酶（PTKS）和磷酸酶（PTPS）平衡作用的结果。 PTK众所周知，是FLS生长和侵入性的关键介体，最近，它们正在成为RA的有前途的药物靶标。另一方面，几乎没有在FLS的PTP上完成任何工作。该赠款申请的重点是称为PTPRS的跨膜PTP。 PTPR在造血细胞中以低或无法检测到的水平表达，但我们发现它在FL中高度表达。 PTPR的细胞外域与细胞外基质中的蛋白聚糖结合并与不同蛋白聚糖的结合会导致磷酸酶的细胞内功能差异。这种PTPRS介导的细胞内信号调节机制被称为“蛋白聚糖开关”。我们发现，蛋白聚糖开关以PTPRS依赖性的方式调节FLS的粘附和侵入性。我们还发现，在体内干扰蛋白聚糖开关会导致小鼠模型中关节炎的严重程度降低。我们的工作假设是PTPR是RA FLS破坏性行为的关键调节剂。该项目的目标是将PTPRS建立为FLS中细胞外基质诱导的信号的关键调节剂，并提供原理证明蛋白聚糖开关是RA的药物目标。在AIM 1中，我们将阐明PTPR和蛋白聚糖开关是否影响与AIM 2中RA发病机理有关的FLS病理生理学的各个方面PTPR在AIM 3中以蛋白聚糖依赖性方式控制的途径我们将提供原理证明，靶向PTPR有助于控制体内RA活动，并可以用作抗TNF治疗的组合治疗。该项目的结果将阐明FLS中细胞外基质组成与细胞内信号传导之间的关系。与疾病相关的长期目标是验证一种新的RA靶向组合疗法的方法。