MicroRNA Networks in self-sustaining type 2 airway niches in asthma

哮喘自我维持 2 型气道生态位中的 MicroRNA 网络

• 批准号: 10681275
• 负责人: Karl Mark Ansel
• 金额: $ 54.26万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-15 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10681275
• 关键词: Acceleration; Adopted; Affect; Air; Allergens; Allergic inflammation; Anatomy; Asthma; Basic Science; Binding Sites; Biochemical; Bioinformatics; Biology; CCR6 gene; Cell Differentiation process; Cell Line; Cell Reprogramming; Cells; Characteristics; Collaborations; Critical Pathways; Cytometry; Data; Development; Disease; Drug or chemical Tissue Distribution; Epithelial Cells; Epithelium; Experimental Models; Family; Frequencies; Functional disorder; Gene Expression; Gene Expression Profiling; Genes; Heterogeneity; Homeostasis; Human; Hyperactivity; Immune; Immunologics; In Vitro; Inflammation; Knockout Mice; Laboratories; Liquid substance; Lung; Maps; Mediating; MicroRNAs; Molecular; Molecular Target; Mucous body substance; Mus; Nature; Pathogenesis; Pathologic; Pathologic Processes; Pathology; Pathway interactions; Peripheral; Population; Production; Property; Pulmonary Inflammation; Pulmonary Pathology; RNA; Regulatory T-Lymphocyte; Research; Role; Site; System; T cell differentiation; T-Lymphocyte; T-Lymphocyte Subsets; Technology; Testing; Thymus Gland; Tissues; Translational Research; airway epithelium; airway inflammation; airway obstruction; allergic airway inflammation; cell type; cytokine; gene network; gene regulatory network; genome editing; high dimensionality; immunopathology; immunoregulation; innovation; miRNA expression profiling; molecular marker; mouse model; mucin hypersecretion; mucus hypersecretion; novel; prevent; programs; response; single cell mRNA sequencing; transcriptomics

Project Summary Th2 high asthma is defined by persistent airway inflammation that is driven by cytokine crosstalk between epithelial cells and tissue resident innate and adaptive immune cells. The central theme of our collaborative research program is that the focal nature of type 2 inflammation that occurs in asthma reflects the development of persistent type 2 airway niches containing reprogrammed epithelial and immune cells. Disrupting these niches may durably impact asthma pathogenesis. Under normal conditions, transient type 2 responses operate to maintain epithelial barrier function. In asthma, regulatory mechanisms that dampen these responses fail, and type 2 inflammation with epithelial cell reprogramming and mucin hypersecretion persists at focal sites in the airways. The central objective of this project is to define molecular determinants of cell reprogramming that sustain persistent immunopathology in Th2-high asthma. The proposed studies focus on two cell types whose programming directly affects this pathological process: T regulatory (Treg) cells and airway epithelial cells. Our approach builds upon preliminary data indicating that type 2 inflammation and lung dysfunction correlate inversely with the frequency of a subset of airway Tregs, and the positive identification of distinct miRNA families that control the programming of Tregs and epithelial cells. The project is organized into three aims: In Aim 1, we will use single cell sequencing, mRNA and miRNA profiling and mass cytometry to define airway Treg populations, and to compare Treg subsets in persistent airway type 2 niches marked by focal sites of mucus impaction with those that populate unaffected airways. In Aim 2, we will dissect Treg programming using miRNA-directed pathway discovery, a novel experimental framework for probing miRNA:target gene networks. A similar approach will be applied in human airway epithelial cells in Aim 3 to reveal miRNA:target networks that control the cell reprogramming and mucin hypersecretion that marks airway type 2 niches in asthma. If successful, the proposed research will uncover novel genes and pathways critical to the pathology of asthma, advance our understanding how immune regulation mechanisms fail in type 2 airway niches, and suggest strategies to disrupt the inflammation that sustain this disease.

项目概要 Th2 高哮喘的定义是由细胞因子串扰驱动的持续性气道炎症。 上皮细胞和组织驻留先天性和适应性免疫细胞。我们合作的中心主题 研究计划是，哮喘中发生的 2 型炎症的焦点性质反映了哮喘的发展 含有重新编程的上皮细胞和免疫细胞的持续性2型气道微环境。破坏这些利基市场 可能会持久影响哮喘发病机制。在正常情况下，瞬态 2 型响应可实现 维持上皮屏障功能。在哮喘中，抑制这些反应的调节机制失效了，并且 伴有上皮细胞重编程和粘蛋白分泌过多的 2 型炎症持续存在于 航空公司。该项目的中心目标是定义细胞重编程的分子决定因素 维持 Th2 高哮喘的持续免疫病理学。 拟议的研究重点关注两种细胞类型，它们的编程直接影响这种病理过程： 调节性 T (Treg) 细胞和气道上皮细胞。我们的方法建立在初步数据的基础上，表明 2 型炎症和肺功能障碍与气道 Tregs 子集的频率呈负相关，并且 积极鉴定出控制 Tregs 和上皮细胞编程的不同 miRNA 家族。 该项目分为三个目标： 在目标 1 中，我们将使用单细胞测序、mRNA 和 miRNA 分析 和质谱流式细胞仪来定义气道 Treg 群体，并比较 2 型持续性气道中的 Treg 亚群 以粘液嵌塞的焦点部位为标志的壁龛，以及未受影响的气道中的壁龛。在目标 2 中，我们将 使用 miRNA 引导的通路发现来剖析 Treg 编程，这是一种新颖的探测实验框架 miRNA：目标基因网络。类似的方法将应用于目标 3 中的人气道上皮细胞 揭示 miRNA：控制细胞重编程和标记气道的粘蛋白过度分泌的靶网络 2型哮喘的利基。如果成功，拟议的研究将发现对生命至关重要的新基因和途径 哮喘的病理学，加深我们对免疫调节机制如何在 2 型气道中失效的理解 利基，并提出了破坏维持这种疾病的炎症的策略。