Project I of this Program Project Grant revised renewal application will address the following hypothesis: HRV wheezing illnesses, working through at least two independent mechanistic pathways, lead to the development of distinct asthma phenotypes that can be characterized immunologically and physiologically and be further modulated over time based on gender and developmental stage of the host. This project will continue prospective immunologic and physiologic asthma phenotyping while simultaneously interrogating two novel findings relating human rhinovirus (HRV) wheezing illnesses to the inception of asthma: preschool HRV wheezing illnesses significantly predict asthma risk at 11 years of age through at least two independent asthma risk pathways that we have termed 17q21 (human chromosomal region) and FceRI (high affinity receptor for IgE antibody) based on their relationships to genetic variation at these loci and to surface expression of FCERI on cord blood mononuclear cells. The mechanisms linking these asthma risk pathways to HRV wheezing and childhood asthma are unclear and of high importance for further study. Project I has been, and will continue to be, the central resource for all projects for the immunologic and physiologic phenotypic characterization in the COAST cohort. It has uncovered alterations in innate immune response patterns that are associated with the frequency and severity of viral respiratory illnesses and loss of lung function related to both HRV infections and gender. Project I will continue to longitudinally evaluate the expression of clinical phenotypes such as persistent wheezing, allergic sensitization, asthma (expression and remission), and atopic dermatitis, and developmentally assess cytokine immune response profiles (using cell culture and state-of-the-art flow cytometry assays) and a variety of physiological measurements including spirometry, impulse oscillometry, fractional exhaled nitric oxide, plethysmography, mannitol challenge and magnetic resonance imaging. The strength of the longitudinal study design and 80% retention rate are critical to understanding the impact of these immunologic and physiologic alterations on changes in asthma prevalence and severity based on age and gender as the cohort approaches puberty and early adulthood.
Asthma is the most common chronic disease in children. As such, understanding mechanisms that lead to asthma inception initially, and exacerbations once the disease is established, is of major relevance in order to better inform the appropriate timing (age and gender) and nature of future prevention studies and to better understand why various therapies may or may not be of benefit to reduce ongoing morbidity and mortality.
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