Role of PTP4A1 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在于 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成纤维细胞转化为α-平滑肌肌动蛋白 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，酶控制 通过从磷酸化酪氨酸中去除磷酸从而平衡蛋白质的作用的信号转导 酪氨酸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称为PTP 4A 1的酪氨酸磷酸酶在细胞中过表达。 与正常成纤维细胞相比，来自系统性硬化症患者的真皮成纤维细胞。我们的初步数据 提示PTP 4A 1在离体和体内真皮成纤维细胞中通过促进 TGF β信号传导。这项拨款提案旨在收集有关分子生物学的试点关键信息。 PTP 4A 1在TGF β信号传导中的作用机制（Aim 1）和PTP 4A 1促进TGF β信号传导的能力 体内实验性纤维化（目的2）。长期目标是验证PTP 4A 1和/或其下游 作为可能的靶点来预防系统性硬化症中的纤维化。

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.