International Mammalian Genome Society

The 15th International Mouse Genome Conference (2001)


POSTER 20 - GENETIC ANALYSIS OF ANTIGEN-INDUCED AIRWAY MANIFESTATIONS OF ASTHMA USING RECOMBINANT CONGENIC MOUSE STRAINS

Dr. Peter C Groot
Utrecht University
Department of Pharmacology
Sorbonnelaan 16
Utrecht 3584 CA
Netherlands

Co-Authors: 1) Groot PC 1) Jeurink PV, 1) Nijkamp FP 2) Demant P  1) Van Oosterhout AJM
Institutions: 1) Dept. of Pharmacology and Pathophysiology, Faculty of Pharmacy, Utrecht University, 2) Div. Molec. Genetics, Netherlands Cancer Institute

Allergic asthma is a heterogeneous and genetically complex disease characterized by allergen-specific IgE, eosinophilic airway inflammation and hyperresponsiveness to bronchospasmogenic stimuli. To facilitate the mapping of genes controlling complex asthma traits we are using the Recombinant Congenic Strains of mice, which offer higher resolution power than standard mouse crosses in mapping segregating QTLs and in detection of their (epistatic) interactions. We are phenotyping 19 CcS/Dem-strains, which each carry a random set of 12.5% of genes from the "Th1-responder" strain STS and 87.5% genes from the "Th2-responder" strain BALB/c. Mice are sensitized with ovalbumin (OVA) and lateron repeatedly challenged by inhalation of OVA aerosol. Before and after OVA challenges, serum is obtained, airway responsiveness to nebulized metacholine (1.5-50 mg/ml) determined, bronchoalveolar lavage (BAL) performed and the number of leukocytes determined.

Preliminary results indicate that there is no correlation between number of BAL eosinophils and extend of airway hyperresponsiveness. Strain 12 displays airway eosinophilia but resistance to hyperresponsiveness. However, baseline airway responsiveness of strain 12 is higher than of other strains tested. In strain 11, airway hyperresponsiveness is predominantly determined by an increased sensitivity (ED300) to metacholine whereas in strain 5 and 18 only a significant increase in the maximal response could be observed. These and other data demonstrate that different "asthma" traits like IgE, eosinophilia and hyperresponsiveness are genetically dissociated. Further mapping studies, using F2-crosses generated between BALB/c and the most interesting CcS/Dem strains will be carried out to localize modifier genes involved in specific "asthma"- traits.

Acknowledgement: Supported by a research grant (AF99.23) of the Dutch Asthma Foundation


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