Airway sensory nerve changes in a mouse model of maternal allergen exposure

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Project Summary Asthma is a pervasive public health problem, and affects over 10% of US citizens including 7 million children. Children born to a mother with asthma have a significantly greater risk of developing asthma than children born to fathers with asthma. This effect cannot be explained by genetic predisposition alone, suggesting there are developmental, in utero exposures that predispose children to developing airway disease. Recently, adults with asthma were found to have increased airway sensory innervation and worse airway obstruction, thus linking airway sensory nerve remodeling to excessive bronchoconstriction in asthma. Furthermore, our preliminary data indicate increased airway innervation develops in utero, suggesting that development of asthma in later life is pre-programmed during fetal development. To study the effects of maternal exposures on fetal development, we established a mouse model in which offspring of mothers exposed to house dust mite allergen throughout pregnancy develop characteristic features of human asthma, including airway hyperreactivity and increased sensory innervation. Airway hyperreactivity is defined as greatly exaggerated bronchoconstriction (narrowing of the airways) in response to inhaled stimuli, and it is mediated by a reflex that includes both sensory and parasympathetic nerves. The goal of this project is to test the specific contribution of sensory nerve remodeling to excessive bronchoconstriction in adult mouse offspring of these allergen exposed mothers, and to determine whether sensory nerve remodeling is reversible in established disease. In this proposal, I will distinguish between the contribution of sensory and parasympathetic nerves to airway reactivity in adult offspring after maternal allergen challenge using pharmacological and surgical techniques, as well as an innovative optogenetic approach that I developed. Since long-lasting airway nerve changes in asthma are likely maintained by nerve growth factors, I propose to block brain derived neurotrophic factor (BDNF), which is known to promote nerve growth and survival and which is also increased in patients with asthma and in offspring from mothers exposed to allergen. I will test whether blocking BDNF reverses the increased airway sensory innervation and airway hyperreactivity using our lab's novel imaging and quantification techniques. Taken together, achieving the goals of this project will: 1) define the neuronal mechanism for airway hyperreactivity in offspring following maternal allergen exposure, 2) identify whether established neuronal remodeling is reversible following BDNF antagonism, and 3) may lead to the development of new therapeutic targets for childhood asthma.