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记物工具和其他翻译 研究观察，以发现系统性硬化症(SSC)患者的新疗法。这个目标可以是 分为四个中间目标：通过翻译了解致病途径 研究，开发SSc的生物标记物，开发新的治疗方法，并应用生物信息学和 系统生物学方法解释翻译和生物标记物数据。在目前的障碍中 寻找治疗SSc新药的进展是对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、 促进SSc患者纤维化和血管损伤的介质和细胞。其中包括非常大的， 纵向临床-生物样本库；SSC肺移植和温热尸检计划；以及皮肤 活组织检查、体外肺灌流、远端肺动脉功能造影和肺组织块培养 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记物，调查 应用单细胞RNA-SEQ技术检测正常皮肤和SSC皮肤间充质细胞异质性，并研究其对 阻断与肌成纤维细胞分化相关的基因。在项目2中，调查人员将检查更改后的 SSC白细胞和肺血管内皮细胞氧化应激和有丝分裂的标志物 取自右心导管术和自发性硬化性心脏病患者的解剖的肺动脉。 伴发肺动脉高压。他们还将调查最近批准的NRF2的影响 富马酸二甲酯对这些系统中的内皮细胞的抑制作用。在项目3中，调查人员将研究 泛素连接酶在SSc相关性间质性肺疾病中的表达他们还将设计 应用定量构效关系筛选SSC-ILD泛素连接酶拮抗剂 这些抑制物在肺外植体和体外肺灌流模型中。AIMS项目将得到三个项目的支持 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 和数据集成核心。后者将综合每个项目和跨项目的数据，以开发 与不同疾病表现相关联的常见分子途径的模型。每一项的重点 在关于不同SSC临床表现、疾病介体和药物抑制剂的项目中，将提供 丰富、高度协作的环境，可在项目主题和核心之间进行基础发现 资源。项目和核心的互补经验将进一步加强这一点 生物采样、生物标记物、转化医学、药物开发、生物信息学和 系统生物学，最终导致了新的靶向疗法的发展。

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.