Asthma is the most common chronic respiratory disease and in many countries prevalence continues to rise. The major cause of asthma morbidity, mortality and health care costs are acute exacerbations, with rhinovirus infection the major cause. The aim of this application is to identify novel targets for the development of new more effective therapies for treatment and prevention of virus-induced asthma exacerbations, a disease area where there is a major unmet current clinical need. This proposal combines two unique state of the art novel models of acute exacerbations of asthma. First, a human model will be used to identify dysregulated genes/proteins and determine relationships with disease outcomes in vivo. This study will compare lower airway responses between asthmatic and control subjects undergoing rhinovirus experimental infection. This will have the dual advantage of investigating mechanisms in the most natural model possible, as well as developing a better model for testing novel therapeutic approaches. The second utilizes a unique new mouse model of rhinovirus infection in which causal relationships with disease outcomes can be investigated in vivo. This will be performed using gene-knockout mice, blocking antibodies, siRNA, pharmacologic inhibition and/or over-expression in genes in a novel mouse model of rhinovirus exacerbation. Any genes/proteins shown to be dysregulated and related to disease outcomes in the human model, AND causally related to disease outcomes in the mouse in vivo model will be very strong candidates for immediate translation of approaches to correct the dysregulation in proof of concept pivotal human intervention studies. The development of a new low dose challenge human model proposed will also provide a new and optimal model of naturally occurring exacerbations, in which such proof of concept pivotal human intervention studies can be carried out.