Host-microbiome interactions in sarcoidosis

结节病中宿主-微生物组的相互作用

• 批准号: 9919615
• 负责人: Cody Adam Schott
• 金额: $ 5.05万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-08 至 2021-05-07
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9919615
• 关键词: Actinobacteria class; Address; Affect; African American; Bacteria; Biological Process; Biological Response Modifiers; Bronchoalveolar Lavage; CD4 Positive T Lymphocytes; Cell Surface Receptors; Cell physiology; Cells; Clinical; Data; Development; Diagnosis; Diagnostic; Disease; Etiology; FOXP3 gene; Foundations; Future; GATA3 gene; Gene Activation; Gene Expression; Genes; Goals; Granuloma; Granulomatous; Healthcare; Heart; Immune; Immune response; Investigation; Laboratories; Lesion; Linear Regressions; Liver; Lower respiratory tract structure; Lung; Lung diseases; Lymphocyte Function; Mediating; Mediator of activation protein; Messenger RNA; Metadata; Metagenomics; Methods; MicroRNAs; Modeling; Pathogenesis; Pathogenicity; Pathology; Population; Production; Proteobacteria; Regression Analysis; Regulation; Regulatory Element; Regulatory T-Lymphocyte; Role; Sampling; Sarcoidosis; Shotgun Sequencing; Skin; Statistical Data Interpretation; Systems Biology; T cell response; T-Lymphocyte; T-Lymphocyte Subsets; United States; Virus; Woman; body system; cytokine; differential expression; fungus; host microbiome; host-microbe interactions; immunoregulation; improved; ineffective therapies; metagenome; microbial genome; microbiome; microbiome sequencing; multiple omics; peripheral blood; predictive modeling; transcriptome; transcriptome sequencing; whole genome

PROJECT ABSTRACT Our goal is to identify significant interactions between the host immune response and the metagenome in sarcoidosis. Sarcoidosis, a disease of unknown etiology, represents an unmet challenge in healthcare. Sarcoidosis is difficult to diagnose, treatments are ineffective, and in the United States it disproportionately afflicts African American women. The disease primarily affects the lungs, but can target the heart, skin, liver and other organ systems as well. Although the etiology remains unknown, dysregulation of T cell subsets in the immune response has been described. Our preliminary data reveal changes in the microbiome and immune regulatory elements as well distinct populations of miRNAs in sarcoidosis providing evidence for the involvement of both the microbiome and immunoregulation. Our hypothesis is that host-microbe interactions are key determinants of aberrant T- lymphocyte function in sarcoidosis. Aim 1 will investigate the role of the metagenome in sarcoidosis. Our preliminary data identifies distinct taxa in the metagenome of bronchoalveolar lavage samples from sarcoidosis subjects. We will use metagenomic shotgun sequencing to identify and quantitate the bacteria, viruses and fungi in sarcoid subjects and perform linear regression analysis to identify significant taxa that are associated with covariates in the metadata. We anticipate that our investigation will identify the composition of the metagenome and also identify biologic functions that are diagnostic of sarcoidosis. Aim 2 will analyze interactions between the host immune response and the metagenome. To investigate the regulatory T cell response in sarcodosis, we will perform RNAseq to identify modulated mRNA and also miRNA. The differentially expressed genes will be used in conjunction with the results of Aim 1 to identify mechanistic functions and to construct predictive models of sarcoidosis. Overall, we will address the interface between the microbiome and T-lymphocyte regulation using a systems biology approach to elucidate key mechanisms of host-microbe interactions contributing to pathology.

项目摘要 我们的目标是确定宿主免疫反应和宏基因组之间的重要相互作用， 结节病结节病是一种病因不明的疾病，是医疗保健领域尚未解决的挑战。 结节病很难诊断，治疗无效，在美国， 非裔美国女性这种疾病主要影响肺部，但也可以靶向心脏，皮肤，肝脏和其他器官。 器官系统也是。虽然病因尚不清楚，但免疫系统中T细胞亚群的失调 已经描述了响应。 我们的初步数据揭示了微生物组和免疫调节元件的变化， 结节病中的miRNAs群体为微生物组和 免疫调节我们的假设是，宿主-微生物相互作用是异常T细胞的关键决定因素， 结节病中的淋巴细胞功能 目的1探讨宏基因组在结节病中的作用。我们的初步数据显示 结节病患者支气管肺泡灌洗样本宏基因组中的分类群。我们将使用宏基因组 鸟枪测序，以鉴定和定量肉样瘤受试者中的细菌、病毒和真菌， 线性回归分析，以识别与元数据中协变量相关的重要分类群。我们 预计我们的研究将确定宏基因组的组成，并确定生物学特性。 诊断结节病的功能。 目的2将分析宿主免疫反应和宏基因组之间的相互作用。探讨 在结节病中的调节性T细胞应答，我们将进行RNAseq以鉴定调节的mRNA， 小RNA。差异表达基因将与目标1的结果结合使用，以鉴定 机制功能和构建结节病的预测模型。 总的来说，我们将使用一种新的方法来解决微生物组和T淋巴细胞调节之间的界面。 系统生物学的方法来阐明宿主-微生物相互作用的病理学的关键机制。