Project 1 - Postnatal Development of Airway Trophic Interactions

University Of California At Davis, Davis CA

Investigators

Linked publications & trials

Abstract

The overall goal of this program since its inception has been to define the pathobiological response of the[unreadable] mammalian respiratory system to the inhalation of ambient concentrations of oxidant air pollutants. The focus[unreadable] of this renewal application will be on mechanisms of environmentally induced asthma in young children, using[unreadable] the model of environmental allergic asthma in infant rhesus monkeys that we have developed through support[unreadable] of this program. Using this model over the previous five years of funding, we have made a number of startling[unreadable] discoveries regarding the effect of chronic ozone exposure on lung development and growth during infancy,[unreadable] including: stunting of airway growth, postnatal loss of airway generations, impaired establishment of the FGF-2[unreadable] ternary signaling complex by basal cells, the failure of epithelial surfaces to innervate, impaired central nervous[unreadable] control, enhancement of the allergic response, airway hyperreactivity, disrupted alveolarization, and airway[unreadable] remodeling. The analytical framework in which all of the studies proposed for this renewal will be conducted is[unreadable] the epithelial/mesenchymal trophic unit, whose cellular components establish trophic interactions via an[unreadable] extracellular signaling complex modulated by the basement membrane zone.[unreadable] The overall hypothesis for this program is that environmental exposure to oxidant air pollutants promotes the[unreadable] development of allergic asthma in the developing lungs of young children and exacerbates its severity by: (1)[unreadable] disrupting the homeostasis within the epithelial/mesenchymal trophic unit and (2) fundamentally compromising[unreadable] the establishment and differentiation of the trophic interactions that promote normal airway growth and[unreadable] development. These changes result from the superimposition of continual cycles of acute injury, inflammation,[unreadable] and repair on the immune response to allergen exposure.[unreadable] This Project will focus on the epithelial and mesenchymal cells (fibroblasts, smooth muscle) and the basement[unreadable] membrane zone within the epithelial/mesenchymal trophic unit, with the following specific aims:[unreadable] 1) Define the impact ozone and allergen exposure during postnatal development on the function of airway[unreadable] epithelium as the principle reactive interface between the environment and the rest of the[unreadable] epithelial/mesenchymal trophic unit.[unreadable] 2) Define the impact of ozone and allergen exposure during postnatal development on the function of the[unreadable] basal cell-basement membrane zone-fibroblast complex as both a mediator and a source of extracellular[unreadable] signaling between luminal epithelium and the matrix within the epithelial/mesenchymal trophic unit.[unreadable] 3) Define the impact of oxidant and allergen exposure during postnatal development on the airway smooth[unreadable] muscle as a responder to signaling from the basal cell-basement membrane zone-fibroblast complex and[unreadable] as a player in generating and maintaining the extracellular signaling milieu.