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

基本信息

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
项目类别：
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

项目摘要

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久性 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败了，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 导向的通路发现来剖析 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。