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：
9182480
负责人：
Nunzio Bottini
金额：
$ 17.05万
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：
2016
资助国家：
美国
起止时间：
2016-07-15 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9182480
关键词：
Address Animal Model Applications Grants Attenuated Autoimmune Diseases Bleomycin Blood Vessels Cells Cellular biology Cicatrix Collagen Complex Data Deposition Dermal Disease Drug Targeting Enzymes Epigenetic Process Equilibrium Fibroblasts Fibrosis Funding Mechanisms Goals Growth Half-Life Human Immune system Injection of therapeutic agent Knock-out Knockout Mice Knowledge Laboratories Lung MADH3 gene MAP2K1 gene MAPK3 gene Mediating Mitogen-Activated Protein Kinase Kinases Mitogen-Activated Protein Kinases Modeling Molecular Mechanisms of Action Mus Myofibroblast Nature Organ PTP4A2 gene PTPN1 gene Pathogenesis Pathway interactions Patients Phosphoric Monoester Hydrolases Platelet-Derived Growth Factor Play Process Protein Tyrosine Kinase Protein Tyrosine Phosphatase Proteins Regulation Reporting Role Secondary to Signal Pathway Signal Transduction Skin Smad Proteins Smooth Muscle Actin Staining Method Staging Systemic Scleroderma Transforming Growth Factor beta Tumor Cell Migration Tyrosine Tyrosine Kinase Inhibitor United States Food and Drug Administration Work design in vivo innovation inorganic phosphate novel novel therapeutics overexpression phosphatase of regenerating liver prevent promoter skin fibrosis stem success

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 in 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 compared to normal fibroblasts. Our preliminary data suggest that PTP4A1 plays a pro-fibrotic function in dermal fibroblasts ex vivo and in vivo by promoting TGFbeta signaling. This grant proposal is designed to collect pilot critical information about the molecular mechanism of action of PTP4A1 in TFGbeta signaling (Aim 1) and the ability of PTP4A1 to promote experimental fibrosis in vivo (Aim 2). The long- term goal is to validate PTP4A1 and/or its downstream pathway as possible targets to prevent fibrosis in systemic sclerosis.

抽象的全身性硬化症是一种自身免疫性疾病，其特征是皮肤进行性纤维化和内部纤维化器官。目前尚无FDA批准的剂来防止全身性硬化症中的纤维化进展。全身性硬化的发病机理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在于成纤维细胞中转化生长因子β（TGFBETA）信号通路的过度激活导致过度胶原蛋白沉积和α-光滑肌肉肌动蛋白中成纤维细胞的转化表达肌纤维细胞。我们的实验室专注于蛋白质酪氨酸磷酸酶，即控制的酶通过从磷酸化酪氨酸中去除磷酸盐来转导信号转导，从而平衡蛋白质的作用酪氨酸激酶。酪氨酸磷酸酶在全身性硬化中的作用主要是未经压力的。该项目源于这样的观察，即称为PTP4A1的酪氨酸磷酸酶在与正常成纤维细胞相比，全身性硬化症患者的皮肤成纤维细胞。我们的初步数据建议通过促进PTP4A1在真皮成纤维细胞和体内扮演促纤维化功能 TGFBETA信号传导。该赠款提案旨在收集有关分子的批判性信息 PTP4A1在TFGBETA信号传导中的作用机理（AIM 1）和PTP4A1促进的能力体内实验纤维化（AIM 2）。长期目标是验证PTP4A1和/或其下游尽可能防止全身性硬化症纤维化的途径。