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Role of PTP4A1 in systemic sclerosis

PTP4A1 在系统性硬化症中的作用

基本信息

批准号：
10021705
负责人：
Nunzio Bottini
金额：
$ 58.26万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-20 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10021705
关键词：
Applications Grants Autoimmune Diseases Biochemistry Bleomycin Blood Vessels California Cells Cicatrix Clinical Collagen Complex Data Deposition Dermal Deuterium Disease Disease Progression Drug Targeting Enzymes Equilibrium FDA approved Fibroblasts Fibrosis Goals Grant Immune system Investigation Knock-out Laboratories Lasers Ligation Lung Malignant Neoplasms Mass Spectrum Analysis Modeling Molecular Mothers Mus Myofibroblast NMR Spectroscopy National Institute of Arthritis and Musculoskeletal and Skin Diseases Nature Oncogenic Organ PDGFA gene PTP4A2 gene Pathogenesis Pathogenicity Pathway interactions Patients Pharmacology Phase Phosphoric Monoester Hydrolases Phosphorylation Phosphotransferases Physiological Platelet-Derived Growth Factor Play Productivity Protein Tyrosine Kinase Protein Tyrosine Phosphatase Proteins Publications Pulmonary Fibrosis Regulation Reporting Role San Francisco Signal Pathway Signal Transduction Skin Smooth Muscle Actin Staining Method Specimen Surveys Symptoms Systemic Scleroderma Transforming Growth Factor beta Tyrosine Universities base cohort design extracellular in vivo inorganic phosphate interest novel novel therapeutics overexpression prevent programs promoter skin fibrosis stem targeted agent tumor

项目摘要

ABSTRACT Systemic sclerosis is an autoimmune disease, characterized by progressive fibrosis of the skin and internal organs. There is currently no FDA-approved agent to prevent the progression of fibrosis in systemic sclerosis. The pathogenesis of systemic sclerosis involves a complex interplay of abnormalities of the immune system, blood vessels and fibroblasts. One well-studied mechanism of fibrosis in systemic sclerosis consists of the excessive activation of the transforming growth factor beta (TGFbeta) signaling pathway in fibroblasts, which leads to excessive collagen deposition and transformation of fibroblasts in alpha-smooth muscle actin- expressing myofibroblasts. Our laboratory focuses on protein tyrosine phosphatases, enzymes that control signal transduction by removing phosphate from phosphorylated tyrosines, thus balancing the action of protein tyrosine kinases. The role of tyrosine phosphatases in systemic sclerosis has remained mostly unaddressed. This project stems from the observation that a tyrosine phosphatase called PTP4A1 is overexpressed in dermal fibroblast from systemic sclerosis patients and plays a pro-fibrotic function in fibroblasts ex vivo and in vivo. Mechanistically, PTP4A1 promotes TGFbeta signaling by forming a complex with SRC that inhibits basal SRC auto-phosphorylation and degradation. The objectives of this grant proposal are to dissect the molecular details of the PTP4A1-SRC complex (Aim 1), and to validate PTP4A1 as a key player in SSc fibrosis via experimentation in mice (Aim 2) and further assessment of SSc clinical specimens (Aim 3). The long-term goal is to validate PTP4A1 and/or its downstream pathway as possible targets to prevent and treat fibrosis in systemic sclerosis.

摘要系统性硬化症是一种自身免疫性疾病，其特征在于皮肤和内部的进行性纤维化。机关目前还没有FDA批准的药物来预防系统性硬化症的纤维化进展。系统性硬化症的发病机制涉及免疫系统异常的复杂相互作用，血管和成纤维细胞。系统性硬化症中纤维化的一种充分研究的机制由以下组成：成纤维细胞中转化生长因子β（TGF β）信号通路的过度激活，导致过度的胶原沉积和α-平滑肌肌动蛋白中成纤维细胞的转化，表达肌成纤维细胞。我们的实验室主要研究蛋白酪氨酸磷酸酶，通过从磷酸化的酪氨酸中除去磷酸来进行转导，从而平衡蛋白酪氨酸的作用激酶。酪氨酸磷酸酶在系统性硬化症中的作用仍然没有得到解决。该项目源于观察到一种名为PTP 4A 1的酪氨酸磷酸酶在真皮中过表达，来自系统性硬化症患者的成纤维细胞，并在离体和体内的成纤维细胞中发挥促纤维化功能。从机制上讲，PTP 4A 1通过与SRC形成抑制基础SRC的复合物来促进TGF β信号传导自磷酸化和降解。这项资助计划的目标是剖析 PTP 4A 1-SRC复合物（目的1），并通过实验验证PTP 4A 1作为SSc纤维化的关键参与者在小鼠中（目标2）和进一步评估SSc临床标本（目标3）。长期目标是验证 PTP 4A 1和/或其下游通路作为预防和治疗系统性硬化症纤维化的可能靶点。