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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：
10472538
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/10472538
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 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 Inflammation Pulmonary Pathology RNA 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 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 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.

项目总结