Asthma and Chronic Obstructive Pulmonary Disease (COPD) are the two most common chronic diseases of the airways. Understanding the genetic basisfor these diseaseswill allow us to dissect pathogenetic mechanisms, assess risk, and ultimately lead to individualized therapy. Finding disease genes in animal models of complex human diseases is easier and more cost effective then relying only upon investigation in well characterized human cohorts. Significant variability across mouse strains is observed for both native airways responsiveness and the development of smoke-induced COPD, suggesting a role for genetic determinants of these phenotypes in the mouse. However, in the fields of asthma and COPDresearch, there is a lack of comprehensive strain surveysand too few animalQTL studies to take advantage of the latest genomic and proteomic research that have been developed and utilized to find QTL in other complex human disease. In this project, we will identify genes that influence airway hyperresponsiveness (AHR) and cigarette smoke-induced COPD in mice by surveying36 inbred mousestrains for AHR and COPD. Subsequently, we will employ in silica computationalQTL analysisto detect regions that containAHR and COPD genes, particularly focusing on those genomic regions that influence both AHR and COPD. Based on the computational QTL analysis, we next will select parental strains and carry out actual QTL crosses. Finally, once the QTL have been identified, we will focus on those that are located in positions homologous to human QTL and use several data mining techniques and additionalgenetic crossesto find candidate genes. These candidate genes will be tested for associationin human populations in Projects 1 (asthma) and 2(COPD), thus combining the strengths of the human and mouse systems. We anticipate that providing this strain survey information to the scientific communitywill stimulate additional research in models of asthma and COPD, and will acceleratethe finding of asthma and COPDgenes. Becauseof the high homology between human and mouse locationsfor QTL for commondiseases, including asthma,we hypothesize that a coordinated approach to gene finding using both the animal model and human populations will be more cost-effectiveand successful,and will provide an important infrastructurefor the continuation of genetic research in asthmaandCOPD.
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