Ancillary studies to define dysregulated immune and fibrotic pathways in a well-characterized morphea cohort

项目摘要 Morphea是一种皮肤和皮下组织的自身免疫性疾病。一种不平衡的炎症 反应导致纤维化和萎缩的深层组织，造成身体和心理残疾。 现有的治疗硬斑病的方法并不总是有效的，并且通常与大量的副作用有关。 方面的影响.开发新疗法的最大障碍之一是缺乏研究， morphea的病理生理学，第一步，导致更有针对性的发展， 有效的治疗。成人和儿童睡眠症（MAC）和国家儿童发病登记处 硬皮病（NRCOS）登记研究由主要研究者（分别为Alfrebe和Torok）领导， 已经开始解决这个问题。我们一起工作，研究了蛋白质表达， 使用蛋白质测定，细胞计数， 和微阵列/RNA测序。这些数据表明硬斑病的纤维化是由炎症驱动的 通过IFN-γ介导的基因网络。尽管取得了这一进展，但硬斑病的发病机制，包括 确切的细胞群产生这种IFN-γ过表达，需要深入研究， 治疗方法可以测试。这就是本提案的目标。 我们的研究将利用MAC和NRCOS登记处（美国最大的登记处）的独特资源。 世界），由父母观察队列研究资助（NIAMS R 01）支持， 研究者的多学科和互补专业知识（包括UTSW医疗中心的设施 和匹兹堡大学）进行详细的转录和机制研究，以充分调查 可能的致病细胞类型的转录谱，并研究关键分子的免疫学效应， 成纤维细胞培养物和共培养系统。拟议研究的目标是：1）进一步界定 通过转录组学分析，2）确定这些免疫通路的相关性， 基因签名，以验证临床措施和疾病过程，以评估其作为生物标志物在 3）鉴定表达这些IFN-γ介导的基因的炎性细胞亚群，这些基因可能是 致病细胞亚型，4）确定成纤维细胞亚群及其与致病细胞的相互作用 炎性细胞，5）和定义致病途径，使疾病，通过首先利用人类 成纤维细胞培养。这些研究的进行不仅将探测硬斑病， 机制，但也将产生有前途的目标，为发展生物标志物和新的疗法。

PROJECT SUMMARY Morphea is a disfiguring autoimmune disease of the skin and underlying tissue. An unbalanced inflammatory response leads to fibrosis and atrophy of the deeper tissue, causing physical and psychological disability. Available therapies for morphea are not always efficacious and are often associated with substantial side effects. One of the biggest barriers to the development of new treatments is a lack of studies examining the pathophysiology of morphea, the initial step that leads toward the development of more directed and efficacious therapies. The Morphea in Adults and Children (MAC) and National Registry for Childhood Onset Scleroderma (NRCOS) registries, led by the principal investigators (Jacobe and Torok, respectively), have already begun to address this problem. Working together, we have investigated the protein expression and bulk transcriptional profile associated with morphea in both children and adults using protein assay, cytometry, and microarray/RNA sequencing. These data indicate that fibrosis in morphea is driven by inflammation through a network of IFN-γ mediated genes. Despite this progress, the pathogenesis of morphea, including the exact cell populations’ producing this IFN-γ over expression, needs to be examined in depth before new treatments can be tested. That is the goal of this proposal. Our studies will leverage both the unique resources of the MAC and NRCOS registries (the largest in the world), which are supported by a Parent Observational Cohort study grant (NIAMS R01), and the multidisciplinary and complementary expertise of the investigators (including facilities at UTSW Medical Center and the University of Pittsburgh) to conduct detailed transcriptional and mechanistic studies to fully investigate transcriptional profiles of likely pathogenic cell types and study the immunological effects of key molecules in fibroblast cultures and co-culture systems. The objectives of the proposed studies are to: 1) further define dysregulated immune pathways in morphea via transcriptomic analyses, 2) determine the association of these gene signatures to validated clinical measures and disease course to evaluate their role as biomarkers in morphea, 3) identifying inflammatory cell subsets that express these IFN-γ mediated genes, which are likely the pathogenic cell subtypes, 4) determine fibroblast subsets and their interaction with pathogenic inflammatory cells, 5) and define the pathogenic pathways that enable the disease, by first utilizing human fibroblast cultures. The conduct of these studies will not only probe morphea to find the underlying disease mechanism, but will also produce promising targets for development of biomarkers and new therapies.