Asthma is a common, non-communicable disorder characterized by airway inflammation and airflow obstruction. In addition to environmental triggers and genetic susceptibility, obesity has emerged as a major risk factor for asthma, suggesting that these two chronic diseases may share common mechanisms. In the past few decades, it has become clear that the action of fatty acid binding protein (FABP) aP2 significantly contributes to metabolic diseases associated with obesity, with complementary data produced in both experimental models and in humans. In recent experiments presented here, we detected aP2 in the bronchial epithelium and bronchoalveolar lavage fluid in an allergen-induced model of asthma in mice, and determined that aP2-deficient mice were significantly protected from developing disease in this model. Our overarching hypothesis is that aP2 plays an important role in the development of inflammatory responses and airway hyper-responsiveness in asthma, and in the link between obesity and asthma. The studies described in the current proposal will test this hypothesis by identifying the cellular source and mechanisms of aP2 action (Aim1), determining the impact of circulating aP2 in asthma (Aim2), and finally, by evaluating the efficacy of a small molecule aP2 inhibitor and a neutralizing antibody as asthma therapy (Aim3). Successful completion of the proposed project will not only expand our knowledge related to the pathophysiology of asthma development and the relationship between asthma and obesity, but also may reveal novel mechanisms and new therapeutic approaches against this common disease.
Recent evidence demonstrates that obesity is a major risk factor for the development of asthma. The proposed research will reveal the identity and mechanisms of the molecular players that underlie the connection between these two epidemics. This work will result in a better understanding of airway inflammation in obesity and could lead to the development of new strategies to prevent and manage asthma, reflecting the stated goal of NIH- supported asthma research.
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