Project 3 - Postnantal Development of Airway Neural Control

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/mesenchymai 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 innervation and neural control within the epithelial/mesenchymal trophic unit, with the[unreadable] following specific aims:[unreadable] 1) Determine the impact of O3 and/or house dust mite (HDM) allergen inhalation on the sensory innervation of[unreadable] the conducting airways, its relation to growth factors and cues within the epithelial/mesenchymal trophic[unreadable] unit during critical windows of postnatal development, and whether these changes persist into adult life.[unreadable] 2) Determine the impact of episodic O3 and/or HDM allergen inhalation on the sensory nerve activity arising[unreadable] from multiple airway generations and structures during critical windows of postnatal development and[unreadable] determine whether these changes persist into adult life.[unreadable] 3) Determine the critical window of susceptibility when exposure to O3 and/or HDM allergen results in[unreadable] persistent changes in smooth muscle contractility due to altered neural control.[unreadable] 4) Determine how the early and continued alteration in the balance between sympathetic and[unreadable] parasympathetic nerve activity to airway-associated lymph nodes modulates antigen recognition and[unreadable] lymphocyte phenotype and determine whether this modulation persist into adult life.[unreadable]