Dr. Ewart proposes to investigate the mechanism(s) underlying airway hyperresponsiveness (AHR). This response is well recognized as an essential feature of asthma and other obstructive airway disorders. A genetic predisposition to nonspecific AHR can be demonstrated in humans and in many animal models. While multiple mechanisms may play a role in AHR, building evidence suggests T lymphocyte mediated bronchial inflammation is likely to be a common factor in the development of this response. The general hypothesis governing this proposal is that AHR is regulated by a gene associated with the inflammatory response. The goal is to map the gene that regulates AHR and to begin to elucidate the molecular mechanisms by which alleles at this locus determine AHR in vivo. A natural animal model in which a single autosomal recessive gene (Ach locus) directs acetylcholine mediated AHR in inbred strains of mice is proposed. The first objective will be to evaluate potential mechanisms by which T Iymphocytes mediate AHR. The qualitative and functional relationships between lymphokine production and AHR will, be characterized using reverse transcriptase polymersse chain reaction and transgenic methodologies. The second objective is to describe the detailed map location for the major gene (Ach locus) regulating airway responsiveness in this modeL Random polymorphic DNA markers and potential candidate genes will be evaluated for linkage with the AHR phenotype. These studies can be used to elucidate primary mechanisms establishing the phenotype of AHR, rule out disease mechanisms and suggest hypotheses for localizing human genes controlling AHR.
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