Mechanisms of airway hyperresponsiveness in the offspring of obese mothers

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Project Summary: Offspring of obese mothers are more likely to develop asthma, although the exact molecular mechanisms that determine this relationship remain unclear. We recently have developed a mouse model of maternal obesity that recapitulates metabolic abnormalities seen in offspring seen in humans. Despite being fed solely a regular diet, offspring of obese mother developed hyperinsulinemia, airway epithelium hyperinnervation and reflex airway hyperresponsiveness. Changes in both parasympathetic and sensory nerves are believed to contribute to this hyperresponsiveness. We have previously reported that hyperinsulinemia reduces M2 muscarinic receptor function on airway parasympathetic nerves causing increased acetylcholine release and potentiating parasympathetic nerve-induced bronchoconstriction. It also has been reported that insulin promotes neurite outgrowth, and we have previously shown that increased sensory innervation correlates with disease severity in patients with asthma. Based on these findings, we hypothesize that intrauterine exposure to maternal obesity increases airway innervation and subsequent airway hyperresponsiveness in an insulin- dependent manner. In this project, we will characterize changes in airway neuronal structure and function, neurotransmitter expression, as well as the role of insulin in these changes, by testing the following three specific aims. First, we will test the effect of maternal obesity on airway sensory and parasympathetic nerve function in offspring. Second, we will test the effect of maternal obesity on neuronal architecture, neurotransmitter content and M2 receptor expression in nerves of the offspring. Finally, we will determine the role of insulin in airway hyperresponsiveness and hyperinnervation in the offspring of obese mothers. This project uses cutting edge, innovative techniques developed in our labs and will significantly increase our understanding of the mechanisms of asthma in adult offspring of obese mothers, which will guide us to develop new strategies for specific prevention and treatment in this population.