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.
We will test the idea that an imbalance between immune cells that cause inflammation and others that suppress harmful responses underlies the persistent local lung pathology characteristic of asthma. Our proposed research will map the regulatory gene networks that control the properties of these suppressive cells and the mucus- secreting airway lining cells that are hyperactive in asthma.
| Nusse, Ysbrand M; Savage, Adam K; Marangoni, Pauline et al. (2018) Parasitic helminths induce fetal-like reversion in the intestinal stem cell niche. Nature 559:109-113 |
| Ricardo-Gonzalez, Roberto R; Van Dyken, Steven J; Schneider, Christoph et al. (2018) Tissue signals imprint ILC2 identity with anticipatory function. Nat Immunol 19:1093-1099 |
| Pavord, Ian D; Beasley, Richard; Agusti, Alvar et al. (2018) After asthma: redefining airways diseases. Lancet 391:350-400 |
| Lachowicz-Scroggins, Marrah E; Gordon, Erin D; Wesolowska-Andersen, Agata et al. (2018) Cadherin-26 (CDH26) regulates airway epithelial cell cytoskeletal structure and polarity. Cell Discov 4:7 |
| Bhakta, Nirav R; Christenson, Stephanie A; Nerella, Srilaxmi et al. (2018) IFN-stimulated Gene Expression, Type 2 Inflammation, and Endoplasmic Reticulum Stress in Asthma. Am J Respir Crit Care Med 197:313-324 |
| Peters, Michael C; Ringel, Lando; Dyjack, Nathan et al. (2018) A Transcriptomic Method to Determine Airway Immune Dysfunction in T2-High and T2-Low Asthma. Am J Respir Crit Care Med : |
| Wong-McGrath, Kelly; Denlinger, Loren C; Bleecker, Eugene R et al. (2018) Internet-Based Monitoring in the Severe Asthma Research Program Identifies a Subgroup of Patients With Labile Asthma Control. Chest 153:378-386 |
| Van Dyken, Steven J; Locksley, Richard M (2018) Chitins and chitinase activity in airway diseases. J Allergy Clin Immunol 142:364-369 |
| Dunican, Eleanor M; Elicker, Brett M; Gierada, David S et al. (2018) Mucus plugs in patients with asthma linked to eosinophilia and airflow obstruction. J Clin Invest 128:997-1009 |
| Fassett, Marlys S; Pua, Heather H; Simpson, Laura J et al. (2018) Identification of Functionally Relevant microRNAs in the Regulation of Allergic Inflammation. Methods Mol Biol 1799:341-351 |
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