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: 10360498
• 负责人: Heidi T Jacobe
• 金额: $ 35.87万
• 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/10360498
• 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; Cohort Studies; 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 Type II; Interferons; Lesion; Ligands; Localized scleroderma; Longitudinal Studies; 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; TimeLine; Tissues; United States National Institutes of Health; Universities; Up-Regulation; Work; base; biomarker development; case control; cell type; cohort; cytokine; design; disability; efficacious treatment; expedited review; genetic signature; human tissue; innovation; insight; interest; joint function; macrophage; mouse model; multidisciplinary; neglect; new therapeutic target; novel therapeutics; 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; 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.

项目摘要 Morphea是一种毁容皮肤和下层组织的自身免疫性疾病。一种不平衡的炎症 反应会导致较深的组织的纤维化和萎缩，从而导致身体和心理残疾。 可用的形态疗法并不总是有效的，并且通常与实质性相关 效果。发展新疗法的最大障碍之一是缺乏研究 Morphea的病理生理学，这是导致更有指导性发展和 疗法。成人和儿童的形态（MAC）和童年登记处 由主要研究人员（分别雅各布和托罗克）领导的硬皮病（NRCOS）注册机构已有 已经开始解决这个问题。我们一起研究了蛋白质表达和 使用蛋白质测定，细胞术，与形态相关的批量转录谱与形态相关， 和微阵列/​​RNA测序。这些数据表明形态上的纤维化是由炎症驱动的 通过IFN-γ介导的基因网络。尽管取得了这种进展，但形态的发病机理，包括 确切的细胞种群在表达上产生这种IFN-γ，需要深入研究新的 可以测试治疗。这就是该提议的目标。 我们的研究将利用Mac的独特资源和NRCOS注册机构（其中最大的资源 世界），由父母观察队列研究补助金（NIAMS R01）和 调查人员的多学科和完整的专业知识（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械研究以充分研究 可能致病细胞类型的转录谱并研究关键分子在 成纤维细胞培养和共培养系统。拟议研究的目标是：1）进一步定义 通过转录组分析，形态中的免疫途径失调，2）确定这些关联 验证临床测量和疾病课程的基因签名，以评估其作为生物标志物的作用 morphea，3）识别表达这些IFN-γ介导的基因的炎症细胞亚群，这些基因可能很可能 致病细胞亚型，4）确定成纤维细胞亚群及其与致病性的相互作用 炎性细胞，5），并通过首先利用人类来定义能够使疾病的致病途径 成纤维细胞培养。这些研究的行为不仅会探究morphea发现潜在疾病 机制，但还将为生物标志物和新疗法的开发产生有希望的靶标。