Immune Dysregulation in Sarcoidosis

结节病的免疫失调

• 批准号: 10590750
• 负责人: Kai Huang
• 金额: $ 5.27万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10590750
• 关键词: Albumins; Area; Atlases; Bacillus; Bioinformatics; Biological Assay; Biological Markers; Biomedical Engineering; Biopsy; Cell Communication; Cells; Cellular Assay; Cessation of life; Clinical; Complex; Cutaneous Sarcoidosis; Data; Development; Diagnosis; Disease; Disease Progression; Drug Modelings; Drug Screening; Environment; Etiology; Evaluation; Fostering; Foundations; Future; Gene Expression; Gene Expression Regulation; Genes; Granuloma; Granuloma by Site; Granulomatous; Granulomatous disease; Healthcare; Hyperactivity; Immune; Immune System Diseases; Immune system; Immunology; Immunosuppressive Agents; In Vitro; Inflammatory; Interdisciplinary Study; Laboratories; Lesion; Life; Maintenance; Mediating; Mediator; Modeling; Morbidity - disease rate; Organ; Pathogenesis; Pathogenicity; Pathologic; Pathway Analysis; Patients; Peripheral; Peripheral Blood Mononuclear Cell; Physicians; Play; Population; Process; Proteins; Regulation; Regulatory T-Lymphocyte; Research; Rheumatoid Arthritis; Role; Sampling; Sarcoidosis; Scientist; Skin; Specificity; Symptoms; T-Lymphocyte; Techniques; Tissues; Toxic effect; Training; Treatment Efficacy; Work; anergy; cell type; combinatorial; comparison control; cytokine; design; drug discovery; gene interaction; gene network; immune function; immunoregulation; improved; in vitro Model; indexing; interdisciplinary approach; model design; multidisciplinary; multiple omics; prevent; screening; single-cell RNA sequencing; symptom management; theories; transcriptome; transcriptome sequencing; transcriptomics; tuberculin purified protein derivative; tumor immunology

Abstract Sarcoidosis is a poorly characterized immune disorder that has often been called the “Great Imitator” due to its similarity to a variety of other diseases and the difficulty of diagnosis. The disease causes aggregates of immune cells called granulomas to form in various tissues, causing organ damage and eventual death in severe cases. Sarcoidosis etiology remains largely unknown, with no clear trigger and symptoms that can disappear on their own or worsen despite treatment. Current research has uncovered associations with some common bacterial species as well as immune dysregulation, especially in the T helper 1, T helper 17, and T regulatory cell populations. However, progress in the field has been hampered in part by the complexity of the disease and limitations in current models. We hypothesize that distinct subpopulations of T cells drive immune dysregulation and progression in sarcoidosis. We further hypothesize that this dysregulation differentiates sarcoidosis from other granulomatous processes and provides a basis for disease specific modeling and drug discovery. Aim 1 will apply recently developed single-cell level sequencing techniques to better elucidate the complex network of gene and cell interactions involved in pathogenesis. Samples of sarcoidosis patient granulomas and peripheral blood mononuclear cells (PBMCs) will be analyzed via single-cell RNA sequencing. Their transcriptomes will be compared to the PBMCs of control subjects as well as control granulomas formed by stimulation of control PBMCs with purified protein derivative. Cells will be identified by their gene expression profiles, then assessed for differences in gene expression and regulation in sarcoidosis compared to controls. We will use this data to develop a transcriptomic atlas of cell types and regulatory networks in sarcoidosis. Aim 2 will use this atlas to evaluate in vitro sarcoidosis models which successfully utilized patient samples to elucidate differences between disease and controls. Granulomas created using each model will be analyzed via single-cell RNA-seq and compared to our sarcoidosis transcriptomic atlas. This approach fosters detailed evaluation of the sarcoidosis immune environment and the evaluation of the capability of existing sarcoidosis models to mimic sarcoidosis. This project integrates recent advances in sequencing and bioinformatics to uncover mechanisms involved in sarcoidosis. The single-cell transcriptomic atlas of sarcoidosis granulomas and PBMCs will interrogate cellular interactions that regulate immune dysfunction in sarcoidosis, providing new points of focus for further mechanistic research. Our analysis of sarcoidosis models will guide further model design, and design of high throughput biomarker and drug screens for sarcoidosis. This project has the potential to improve the specificity and efficacy of treatment, as well as the ease of diagnosis. The multidisciplinary research also lays the groundwork for my training as a physician scientist while exploring a key clinical question.

摘要 结节病是一种特征不明显的免疫系统疾病，常被称为“伟大的模仿者”。 由于其与多种其他疾病的相似性和诊断的困难性。这种疾病会导致 在各种组织中形成称为肉芽肿的免疫细胞聚集，导致器官损伤， 严重者死亡。结节病的病因在很大程度上仍然未知，没有明确的触发因素和症状， 可以自行消失或在治疗后恶化。目前的研究发现， 一些常见的细菌种类以及免疫失调，特别是在T辅助细胞1，T辅助细胞17， 和T调节细胞群。然而，这一领域的进展受到阻碍，部分原因是 疾病和现有模型的局限性。 我们假设不同的T细胞亚群会导致免疫失调和疾病进展。 结节病我们进一步假设，这种失调可以将结节病与其他肉芽肿性疾病区分开来。 处理并为疾病特定建模和药物发现提供基础。 目的1将应用最近开发的单细胞水平测序技术，以更好地阐明 发病机制中涉及的基因和细胞相互作用的复杂网络。结节病患者样本 肉芽肿和外周血单核细胞（PBMC）将通过单细胞RNA测序进行分析。 将其转录组与对照受试者的PBMC以及对照受试者形成的肉芽肿进行比较。 通过用纯化的蛋白衍生物刺激对照PBMC。细胞将通过其基因表达来识别 谱，然后评估与对照相比结节病中基因表达和调控的差异。 我们将利用这些数据来开发结节病细胞类型和调控网络的转录组图谱。 目的2将使用该图谱来评价成功利用患者的体外结节病模型 样品，以阐明疾病和对照之间的差异。使用每个模型创建的肉芽肿将 通过单细胞RNA-seq进行分析，并与我们的结节病转录组图谱进行比较。这种方法促进了 详细评估结节病免疫环境和评估现有 结节病模型来模拟结节病。 该项目整合了测序和生物信息学的最新进展， 与结节病有关结节病肉芽肿和PBMC的单细胞转录组图谱将 询问调节结节病免疫功能障碍的细胞相互作用，提供新的焦点 进行进一步的机械研究。我们对结节病模型的分析将指导进一步的模型设计， 设计结节病的高通量生物标志物和药物筛选。这个项目有潜力改善 治疗的特异性和有效性，以及诊断的容易性。多学科研究还 在探索一个关键的临床问题时，为我作为一名内科科学家的训练奠定了基础。