Translational studies for identifying and targeting novel pathways in systemic sclerosis pathogenesis

该研究翻译中心的总体目标是利用生物标志物工具和其他翻译工具， 研究观察，以发现系统性硬化症（SSc）患者的新疗法。这个目标可以 分为四个中间目标：通过翻译理解致病途径 研究，开发SSc的生物标志物，开发新的治疗方法，并应用生物信息学和 系统生物学方法来解释翻译和生物标志物数据。目前的障碍包括 在寻找治疗SSc患者的新药方面取得的进展是对SSc发病机制的认识仍然有限 疾病，部分是由于其复杂性和异质性，部分是由于缺乏良好的动物模型。 匹兹堡大学医学中心和波士顿大学医学中心的创新方案， 获得SSc皮肤和肺生物样本将使研究人员能够发现基因，调节蛋白， 介质和细胞促进SSc患者的纤维化和血管损伤。其中包括非常大的， 纵向临床生物样本库; SSc肺移植和热尸检计划;以及皮肤 活检、离体肺灌注、功能性远端肺动脉造影和肺移植培养 协议.在项目1中，研究人员将验证SSc皮肤和肺部疾病的生物标志物， 使用单细胞RNA-seq在正常和SSc皮肤中的间充质细胞异质性，并研究 阻断与肌成纤维细胞分化相关的基因。在项目2中，研究人员将检查 SSc白细胞和肺血管内皮细胞中氧化应激和线粒体自噬的标志物 在右心导管插入术期间和从SSc患者的夹层肺动脉中获得， 肺动脉高压。他们还将调查最近批准的NRF 2的效果 抑制剂富马酸二甲酯对这些系统中内皮细胞的影响。在项目3中，研究人员将研究 泛素连接酶在Ssc相关间质性肺病（SSc-ILD）中的表达。他们还将设计 使用定量结构-活性关系优化SSc-ILD的泛素连接酶拮抗剂，并测试 这些抑制剂在肺外植体和离体肺灌注模型中。项目目标将得到三个方面的支持 资源核心：临床和生物标本核心，肺组织核心和翻译基因组学 数据集成核心后者将综合来自每个项目和跨项目的数据， 与不同疾病表现相关的常见分子途径的模型。每个人的焦点 的不同SSc临床表现，疾病介质和药物抑制剂的项目将提供一个 丰富、高度协作的环境，用于在桥接项目主题和核心 资源这将进一步加强项目和核心的互补经验 生物取样、生物标志物、转化医学、药物开发、生物信息学和 系统生物学，在新的，有针对性的治疗方法的发展达到高潮。

The overall goal of this Center of Research Translation is to utilize biomarker tools and other translational research observations to discover new therapies for patients with systemic sclerosis (SSc). This goal can be broken down into four intermediate objectives: understanding pathogenic pathways through translational studies, developing biomarkers for SSc, developing novel therapeutics, and applying bioinformatic and systems biology approaches to interpret translational and biomarker data. Among current obstacles to progress in finding new drugs for SSc patients is the continuing limited understanding of pathogenesis of SSc disease, in part due to its complexity and heterogeneity, and in part due to the lack of good animal models. Innovative protocols of University of Pittsburgh Medical Center and Boston University Medical Center for obtaining SSc skin and lung biosamples will allow investigators to discover the genes, regulatory proteins, mediators and cells that promote fibrosis and vascular injury in SSc patients. These include very large, longitudinal clinical-biological sample repositories; SSc lung transplant and warm autopsy programs; and skin biopsy, ex vivo lung perfusion, functional distal pulmonary arterial myography and lung explant culture protocols. In Project 1 investigators will validate biomarkers of SSc skin and lung disease, investigate mesenchymal cell heterogeneity in normal and SSc skin using single cell RNA-seq, and study the effect of blocking genes associated with myofibroblast differentiation. In Project 2 investigators will examine altered markers of oxidative stress and mitophagy in SSc leukocytes and pulmonary vascular endothelial cells obtained during right heart catheterization and from dissected pulmonary arteries of patients with SSc- associated pulmonary arterial hypertension. They will also investigate the effect of the recently approved Nrf2 inhibitor, dimethyl fumarate, on endothelial cells in these systems. In Project 3 investigators will study expression of ubiquitin ligases in SSc-associated interstitial lung disease (SSc-ILD). They will also design optimal ubiquitin ligase antagonists for SSc-ILD using quantitative structure-activity relationships, and test these inhibitors in lung explant and ex vivo lung perfusion models. Project aims will be supported by three resource cores: a Clinical and Biological Specimen Core, a Lung Tissue Core and a Translational Genomics and Data Integration Core. The latter will synthesize data from each project and across projects, to develop models for common molecular pathways associated with different disease manifestations. The focus of each of the projects on different SSc clinical manifestations, mediators of disease, and drug inhibitors will provide a rich, highly collaborative environment for fundamental discovery within bridging project topics and core resources. This will be further enhanced by the complementary experience of the project and core investigators in biosampling, biomarkers, translational medicine, drug development, bioinformatics and systems biology, culminating in the development of new, targeted therapeutics.