Current Active Projects
The Debley Lab's current active projects include:
Dysregulated Airway Epithelial Signaling as a Driver of Airway Remodeling in Asthmatic Children
NIH/NHLBI R01HL128361 (Debley – Principal Investigator)
Using airway epithelial cell/fibroblast co-culture model systems with primary bronchial epithelial cells (BECs) from carefully characterized asthmatic and healthy children we are investigating the role of epithelial stimulatory and inhibitory signals that regulate fibroblasts and airway interstitial extracellular matrix deposition involved in asthmatic airway remodeling.
We are using BEC/fibroblast co-culture model systems with primary BECs from well-characterized asthmatic and healthy children to test our hypotheses that in normal airways a balance of epithelial-secreted stimulatory and inhibitory factors regulate fibroblasts and inhibit FMT, limiting extracellular matrix (ECM) deposition. Furthermore, we are testing our hypotheses that FMT, fibroblast proliferation and ECM expression, and BEC secretion of factors regulating fibroblasts, are associated with asthma severity, exacerbations, and/or lung function among the asthmatic BEC donors.
Epithelial control of responses to allergen challenge and viral exacerbation
NIH/NIAID U19AI125378 – Asthma and Allergic Diseases Cooperative Research Center Grant (U19)
The global hypothesis of this Center grant is that in the context of allergenic sensitization to aeroallergens, the airway epithelium serves as the central coordinator of responses to respiratory viral infection, leading to persistent asthma. Intrinsic differences between airway epithelial cells (AECs) from healthy and asthmatic individuals appear to play a critical role in the development of airway dysfunction. AECs from asthmatics respond in a different manner to infection by respiratory viruses than do AECs from healthy subjects. These differences are manifested during infection in several ways, including changes in the expression and deposition of extracellular matrix components and qualitative and quantitative differences in the expression of cytokines and chemokines. This altered response in asthmatic AECs may lead to changes in both innate and adaptive responses during infection, with increased infiltration of the airways with leukocytes. The primary goal of this Center is to identify and characterize these changes in pediatric and adult asthmatic AECs, and determine their effects on matrix formation and the innate and adaptive immune response.
U19 Project 1: Epithelial regulation of ECM and leukocyte adhesion in viral-triggered asthma (Debley – SCRI Principal Investigator)
In this U19 Center project we will investigate the role of AEC-derived TGFβ in regulating airway extracellular matrix (ECM) composition, including regulation of versican (VCAN) and hyaluronan (HA) accumulation and their degradation products in the airway ECM leading to increased adhesion and activation of inflammatory leukocytes. We hypothesize that viral infection and allergen exposure with the common of AECs from asthmatic as compared to healthy children induce human lung fibroblasts (HLFs) to produce an airway ECM enriched with VCAN, HA and their degradation products, leading to increased adhesion and activation of inflammatory leukocytes. Using human pediatric AEC and AEC/HLF co-cultures we will determine the effects of viral infection and aeroallergen exposure on asthmatic AEC regulation of HLF ECM production and composition.
U19 Epithelial Cell Culture and Airway Translational Core (Debley – SCRI Principal Investigator)
This U19 Core will assist investigators of the Center test the hypothesis that the airway epithelium serves as a central coordinator of the responses to respiratory virus infection, and that sensitization to aeroallergens and intrinsic differences in AECs between asthmatic and healthy individuals is the critical link between exposure and the development of dysfunctional airway responses in asthma. At Seattle Children's Research Institute this Core will serve the Center by:
- Providing access to primary human airway epithelial cells from well-characterized asthmatic and healthy children
- Providing the platform to conduct mechanistic experiments utilizing differentiated human airway epithelial cells in organotypic culture, for in vitro studies with lung stromal cells and leukocytes to support the aims of the Center projects proposed in this grant
- Extensively phenotyping the children enrolled in the Core to provide detailed clinical information about the children from whom airway epithelial cells are isolated to assist in the design, conduct, and analysis of in vitro experiments stratified by the clinical phenotypes and disease severity
TSLP and the Pathophysiology of Asthma
In collaboration with Dr. Steven Ziegler at Benaroya Research Institute, we are investigating the role of TSLP in the pathophysiology of asthma. Using primary pediatric airway epithelial cell air-liquid interface culture systems the aims of the project include
- Determine the role of TSLP in respiratory virus-mediated inflammation and exacerbations.
- Determine the role of TSLP in the response to chronic allergen challenge.
Unique gene expression patterns by asthmatic airway epithelial cells in response to respiratory syncytial virus (RSV) infection
(Debley – Principal Investigator)
In collaboration with Amgen, Inc., and the Benaroya Research Institute we are investigating gene expression patterns of asthmatic bronchial epithelial cells in response to in vitro infection with respiratory syncytial virus (RSV), and associations between epithelial gene response patterns and clinical characteristics of airway epithelial cell donors (e.g., lung function measures, asthma exacerbation patterns, allergic sensitization).
Development of a Vaccine for Viral Exacerbation of Asthma
(Lindell – Principal Investiagator; NIH/NHLBI R01HL111589)
Using nasal airway epithelial cells from asthmatic and healthy children differentiated at an air-liquid interface, we are assisting Seattle Children's Research Institute's Dr. Dennis Lindell in efforts to develop a vaccine for RSV-triggered exacerbation of asthma.
Investigating the Secretome of the Asthmatic Epithelium
In collaboration with Seattle Children's Research Institute's Dr. Richard James, we are investigating differences in airway epithelial cell proteomics signatures between cells from asthmatic and healthy children, at baseline and in response to viral infection.
Participate in Research
Help us answer questions about childhood health and illness, and help other children in the future. See our current research studies.