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: 10226877
• 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/10226877
• 关键词: Adopted; Affect; Air; Allergens; Allergic inflammation; Anatomy; Asthma; Basic Science; Binding Sites; Biochemical; Bioinformatics; Biology; CCR6 gene; Cell Differentiation process; Cells; Characteristics; Collaborations; Critical Pathways; Cytometry; Data; Development; Disease; Drug or chemical Tissue Distribution; Epithelial; Epithelial Cells; 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; Lung Inflammation; Maps; Mediating; Messenger RNA; MicroRNAs; Molecular; Molecular Target; Mucous body substance; Mus; Nature; Pathogenesis; Pathologic; Pathologic Processes; Pathology; Pathway interactions; Peripheral; Population; Production; Property; Pulmonary Pathology; RNA; Regulator Genes; Regulatory T-Lymphocyte; Research; Role; Site; System; T-Lymphocyte; Technology; Testing; Thymus Gland; Tissues; Translational Research; airway epithelium; airway inflammation; allergic airway inflammation; cell type; cytokine; experimental study; genome editing; high dimensionality; immunopathology; immunoregulation; innovation; miRNA expression profiling; molecular marker; mouse model; mucin hypersecretion; mucus hypersecretion; novel; prevent; programs; response; single cell 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.

项目摘要 Th2高哮喘的定义是由细胞因子串扰引起的持续性呼吸道炎症。 上皮细胞和组织驻留的先天免疫细胞和获得性免疫细胞。我们合作的中心主题是 研究计划是，哮喘中发生的2型炎症的局灶性反映了 含有重新编程的上皮细胞和免疫细胞的持久性2型气道壁龛。颠覆这些利基市场 可能对哮喘的发病机制产生持久的影响。在正常情况下，瞬变类型2反应的操作 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，并且 伴有上皮细胞重编程和粘蛋白高分泌的2型炎症持续在病灶部位。 航空公司。这个项目的中心目标是定义细胞重新编程的分子决定因素 持续免疫病理学在Th2高哮喘中的作用。 建议的研究集中在两种细胞类型上，它们的编程直接影响这一病理过程： T调节(Treg)细胞和呼吸道上皮细胞。我们的方法建立在初步数据表明的基础上 2型炎症和肺功能障碍与部分气道树的出现频率呈负相关，并且 控制树突状细胞和上皮细胞编程的不同miRNA家族的阳性鉴定。 该项目分为三个目标：在目标1中，我们将使用单细胞测序、信使核糖核酸和miRNA分析 和质量细胞术来确定气道Treg群体，并比较持续性呼吸道2型Treg亚群 以粘液嵌塞部位为标志的壁龛，与那些填充在未受影响的呼吸道的部位相同。在目标2中，我们将 使用miRNA引导的通路发现--一种新的探测实验框架--剖析Treg编程 MiRNA：靶基因网络。类似的方法将应用于人类呼吸道上皮细胞，目标3至 揭示miRNA：控制细胞重新编程和标志呼吸道的粘蛋白高分泌的靶网络 哮喘中的2型生态位。如果成功，这项拟议的研究将发现关键的新基因和途径 哮喘的病理学，促进了我们对2型呼吸道免疫调节机制失败的理解 利基，并提出了破坏维持这种疾病的炎症的策略。