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

辅助研究，以确定特征明确的硬斑病队列中失调的免疫和纤维化途径

• 批准号: 10580012
• 负责人: Heidi T Jacobe
• 金额: $ 32.48万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10580012
• 关键词: Address; Adult; Ancillary Study; Appearance; Atrophic; Autoimmune Diseases; Automobile Driving; Biological; Biological Assay; Biological Markers; Biopsy; Bleomycin; Blood Cells; CXC chemokine receptor 3; CXCL9 gene; CXCR3 gene; Cells; Child; Childhood; Clinical; Coculture Techniques; Collagen; Cytometry; Data; Development; Disease; Drug Targeting; Feedback; Fibroblasts; Fibrosis; Functional disorder; Future; Gene Expression Profile; Genes; Genetic Transcription; Goals; Grant; Human; Immune; Immunologics; Inflammation; Inflammatory; Inflammatory Response; Infrastructure; Interferon Activation; Interferon Type II; Interferons; Lesion; Ligands; Localized scleroderma; Longitudinal Studies; Macrophage; Maps; Measures; Mediating; Medical center; Modeling; Molecular; Morphea; Mus; National Institute of Arthritis, and Musculoskeletal, and Skin Diseases; Outcome; Parents; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Patient Care; Patient Recruitments; Patients; Phenotype; Population; Positioning Attribute; Principal Investigator; Proteins; Registries; Research Personnel; Resources; Role; Sampling; Signal Transduction; Skin; Skin Tissue; System; T-Lymphocyte; Technology; Testing; Time; Tissues; United States National Institutes of Health; Universities; Up-Regulation; Work; biomarker development; case control; cell type; cohort; cytokine; design; disability; efficacious treatment; expedited review; genetic signature; human tissue; innovation; insight; interest; joint function; mouse model; multidisciplinary; neglect; new therapeutic target; novel therapeutics; observational cohort study; overexpression; peripheral blood; protein expression; psychologic; receptor; recruit; response; scleroderma registry; side effect; single-cell RNA sequencing; skin disorder; skin fibrosis; soft tissue; targeted treatment; therapeutic development; timeline; tool; transcriptome; transcriptome sequencing; transcriptomics; translational study; treatment response

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.

项目总结 吗啡是一种皮肤和底层组织的毁容自身免疫性疾病。一种不平衡的炎症 反应会导致深层组织的纤维化和萎缩，导致身体和心理上的残疾。 现有的治疗吗啡的方法并不总是有效的，而且往往与实质性的副作用有关 效果。开发新疗法的最大障碍之一是缺乏研究 吗啡的病理生理学，这是导致更多定向和 有效的治疗方法。成人和儿童的睡眠(MAC)和国家儿童发病登记 由主要调查员(分别为Jacobe和Torok)领导的硬皮病(NRCOS)登记处 已经开始解决这个问题。共同努力，我们研究了蛋白质的表达和 在儿童和成人中使用蛋白质分析、细胞分析、 和微阵列/RNA测序。这些数据表明，吗啡中的纤维化是由炎症驱动的。 通过干扰素-γ介导的基因网络。尽管取得了这些进展，但吗啡的发病机制，包括 产生这种干扰素-γ过度表达的确切细胞群，需要在新的 治疗方法是可以测试的。这就是这项提案的目标。 我们的研究将利用MAC和NRCOS注册处的独特资源(在 世界)，由父母观察队列研究补助金(NIAMS R01)支持，以及 调查人员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，以全面调查 可能致病细胞类型的转录谱并研究关键分子的免疫学作用 成纤维细胞培养和共培养系统。拟议研究的目标是：1)进一步界定 通过转录转录分析在吗啡中调节失调的免疫途径，2)确定它们之间的联系 基因签名以验证临床测量和病程，以评估它们作为生物标志物在 吗啡，3)识别表达这些干扰素-γ介导的基因的炎性细胞亚群，这些亚群可能 致病细胞亚型，4)决定成纤维细胞亚群及其与致病细胞的相互作用 炎性细胞，并定义致病途径，首先利用人类 成纤维细胞培养。这些研究的进行不仅将探索吗啡以找到潜在的疾病 机制，但也将产生开发生物标记物和新疗法的有希望的靶点。