Role of PTPRS in Rheumatoid Arthritis

PTPRS 在类风湿关节炎中的作用

• 批准号: 10705192
• 负责人: Nunzio Bottini
• 金额: $ 45.73万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 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 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10705192
• 关键词: Address; Aggressive behavior; Antirheumatic Agents; Arthritis; Binding; Biochemical; Biological Assay; Biology; Cell Line; Cells; Cellular biology; Clinic; Coculture Techniques; Cytoskeletal Proteins; Cytoskeleton; Data; Degenerative polyarthritis; Development; Dimerization; Disease; Disease remission; Drug Targeting; Electrons; Endothelial Cells; Endothelium; Enzymes; Epigenetic Process; Extracellular Domain; Fibroblasts; Funding; Genes; Genetic Transcription; Glycosaminoglycans; Goals; Grant; Heparan Sulfate Proteoglycan; Heparitin Sulfate; Human; Immune; Immunoglobulin Domain; Immunosuppressive Agents; In Vitro; Incubated; Inflammation; Invaded; Joints; Knowledge; Lead; Mediating; Membrane; Microscopy; Molecular; Morbidity - disease rate; Mus; Nature; Pathway interactions; Patients; Pattern; Permeability; Phenotype; Phosphoric Monoester Hydrolases; Phosphorylation; Play; Protein Dephosphorylation; Protein Family; Protein Tyrosine Kinase; Protein Tyrosine Phosphatase; Proteins; Proteoglycan; Publishing; Regulation; Reporting; Rheumatoid Arthritis; Role; Series; Side; Signal Transduction Inhibition; Surface; Swelling; Synovial Membrane; TNF gene; Therapeutic; Therapeutic Agents; Translating; Validation; Work; arthritis therapy; cell behavior; cell motility; design; disorder control; extracellular; ezrin; immunoregulation; imprint; in vivo; innovation; interest; joint destruction; joint inflammation; joint injury; migration; mouse model; neutrophil; novel; novel therapeutics; overexpression; polysulfated glycosaminoglycan; protein expression; recruit; structural biology; syndecan-4; therapeutic target

ABSTRACT Fibroblast-like synoviocytes (FLS) are joint-lining non-hematopoietic cells that in rheumatoid arthritis (RA) contribute to local joint inflammation and damage. There is interest in discovering FLS-directed therapeutic agents that could be combined with current immunosuppressant disease-modifying anti-rheumatic agents (DMARDs). This renewal proposal focuses on understanding the mechanism of action and regulation of the tyrosine phosphatase PTPRS, which plays a critical role in FLS migration and invasion. In the first cycle of this grant, we have shown that PTPRS is an important regulator of FLS aggressiveness during RA and developed an approach to modulate PTPRS function in rheumatoid FLS. Our studies showed that on the surface of RA FLS, PTPRS is kept in an inactive state through specific binding to the heparan sulfate (HS)- proteoglycan syndecan-4 through a mechanism called the proteoglycan switch. Treatment of RA FLS with a decoy fragment of PTPRS encompassing its two most extracellular proteoglycan-binding immunoglobulin domains (called Ig1&2) causes detachment of PTPRS from syndecan-4. This leads to PTPRS-dependent inhibition of migration and invasiveness via dephosphorylation of the PTPRS substrate ezrin. In vivo administration of Ig1&2 reverses arthritis in multiple mouse models via a non-immunological mechanism. We also find that PTPRS expression is inhibited on RA FLS by tumor necrosis factor alpha, suggesting that PTPRS expression is regulated by joint inflammation. In the second cycle of the grant, we would like to deepen our knowledge of the mechanism of action and regulation of PTPRS in FLS and RA. Here we propose to a series of mechanistic studies in primary human FLS and mouse models of RA aimed at understanding the regulation of PTPRS expression in RA FLS (Aims 1) and how Ig1&2 and PTPRS regulate FLS-induced inflammation in arthritis (Aim 2). We will also use biochemical, structural, and cellular biology approaches to understand the key molecular determinants for PTPRS regulation by syndecan-4 (Aim 3). Our long-term goal remains to understand the biology of PTPRS in RA FLS, which will help to complete the validation of the PTPRS-regulated pathway as a therapeutic target for RA.

抽象的 成纤维细胞样的滑膜细胞（FLS）是类风湿关节炎（RA）的联合衬里非脊髓性细胞 有助于局部关节炎症和损害。有兴趣发现FLS指导的治疗性 可以与当前免疫抑制剂疾病改良剂结合的药物 （dmards）。该更新提案的重点是理解行动机理和调节的机理 酪氨酸磷酸酶PTPR在FL的迁移和侵袭中起着至关重要的作用。 在这笔赠款的第一个周期中，我们表明PTPR是FLS侵略性的重要调节者 RA并开发了一种调节类风湿FL中PTPR功能的方法。我们的研究表明 通过特异性结合硫酸乙酰肝素（HS） - 蛋白聚糖Syndecan-4通过称为蛋白聚糖开关的机制。用 PTPR的诱饵片段涵盖了其两个最细胞外蛋白聚糖结合免疫球蛋白 域（称为Ig1和2）导致PTPR脱离Syndecan-4。这导致依赖PTPR PTPRS底物Ezrin的去磷酸化对迁移和侵入性的抑制。体内 Ig1和2的给药通过非免疫学机制逆转了多种小鼠模型中的关节炎。我们 还发现肿瘤坏死因子alpha抑制了PTPRS的表达，这表明PTPRS 表达受关节炎症调节。 在赠款的第二个周期中，我们想加深对行动机理的了解和 PTPR在FLS和RA中的调节。在这里，我们建议在原代人FLS中进行一系列机械研究 RA的小鼠模型旨在了解RA FL中PTPRS表达的调节（AIMS 1）和 Ig1和2和PTPR如何调节FLS诱导的关节炎炎症（AIM 2）。我们还将使用生化， 结构和细胞生物学方法了解PTPRS调控的关键分子决定因素 由Syndecan-4（AIM 3）。 我们的长期目标仍然是了解RA FLS中PTPR的生物学，这将有助于完成 验证PTPRS调节的途径是RA的治疗靶标。

项目成果

Receptor Protein Tyrosine Phosphatase α-Mediated Enhancement of Rheumatoid Synovial Fibroblast Signaling and Promotion of Arthritis in Mice.

• DOI: 10.1002/art.39442
• 发表时间: 2016-02
• 期刊: Arthritis & rheumatology (Hoboken, N.J.)
• 作者: Stanford SM;Svensson MN;Sacchetti C;Pilo CA;Wu DJ;Kiosses WB;Hellvard A;Bergum B;Muench GR;Elly C;Liu YC;den Hertog J;Elson A;Sap J;Mydel P;Boyle DL;Corr M;Firestein GS;Bottini N
• 通讯作者: Bottini N

Targeting Tyrosine Phosphatases: Time to End the Stigma.

• DOI: 10.1016/j.tips.2017.03.004
• 发表时间: 2017-06
• 期刊: Trends in pharmacological sciences
• 影响因子: 13.8
• 作者: Stanford SM;Bottini N
• 通讯作者: Bottini N

RPTPα phosphatase activity is allosterically regulated by the membrane-distal catalytic domain.

RPTPα 磷酸酶活性受膜远端催化域变构调节。

• DOI: 10.1074/jbc.ra119.011808
• 发表时间: 2020
• 期刊: The Journal of biological chemistry
• 作者: Wen,Yutao;Yang,Shen;Wakabayashi,Kuninobu;Svensson,MattiasND;Stanford,StephanieM;Santelli,Eugenio;Bottini,Nunzio
• 通讯作者: Bottini,Nunzio