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：
10199030
负责人：
Nunzio Bottini
金额：
$ 58.24万
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 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10199030
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.

抽象的系统性硬化症是一种自身免疫性疾病，其特征是皮肤和内部进行性纤维化器官。目前尚无 FDA 批准的药物可以预防系统性硬化症纤维化的进展。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经过充分研究的机制包括成纤维细胞中转化生长因子β（TGFβ）信号通路的过度激活，导致α-平滑肌肌动蛋白中胶原蛋白过度沉积和成纤维细胞转化表达肌成纤维细胞。我们的实验室专注于蛋白质酪氨酸磷酸酶，即控制信号的酶通过从磷酸化酪氨酸中去除磷酸盐进行转导，从而平衡蛋白质酪氨酸的作用激酶。酪氨酸磷酸酶在系统性硬化症中的作用仍未得到解决。该项目源于对一种名为 PTP4A1 的酪氨酸磷酸酶在真皮中过度表达的观察来自系统性硬化症患者的成纤维细胞，在体外和体内的成纤维细胞中发挥促纤维化功能。从机制上讲，PTP4A1 通过与 SRC 形成复合物来抑制基础 SRC，从而促进 TGFbeta 信号传导自身磷酸化和降解。该拨款提案的目的是剖析分子细节 PTP4A1-SRC 复合物（目标 1），并通过实验验证 PTP4A1 作为 SSc 纤维化的关键参与者在小鼠中进行实验（目标 2）并进一步评估 SSc 临床标本（目标 3）。长期目标是验证 PTP4A1 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。