A function of the neuroendocrine system in mucous hyperplasia

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 DESCRIPTION (provided by applicant): Childhood asthma is steadily increasing worldwide. Risk factors include early-life airway insults by pollutants, cigarette smoke, respiratory viral infection, and allergen exposure. Clinical hallmarks of asthma include TH2 inflammation, airway hyper-reactivity and mucous hyperplasia. Mucous hyperplasia is a major contributor to cause of death in patients suffering from asthma. Currently, there is no cure for asthma-with available drugs only alleviating airway inflammation and bronchoconstriction but no treatment directly targeting mucous hyperplasia. To develop better therapies for asthma, the mechanism behind mucous overproduction needs to be fully understood. Mucus serves as a first line of defense to protect and clear the lung from potential pathogens or toxic substances. In asthma, however, mucous hyperplasia results in airway obstruction contributing to mortality. Mucin proteins, such as MUC5AC, are predominantly synthesized by goblet cells that line the epithelium. In asthma, inflammatory signals including epidermal growth factor (EGF) and IL-13, are known to induce trans-differentiation of club cells and ciliated cells to mucin-producing goblet cells. In additionto these inflammatory signals, mucous hyperplasia in mouse models of asthma requires GABA, a central neurotransmitter. Consistently, GABA signaling is aberrantly upregulated in the airway of asthmatic patients and by cigarette smoke. This supports a role for deregulated GABA signaling in mucous hyperplasia, but how GABA signaling contributes to mucous hyperplasia is poorly understood. Our preliminary studies show that neuroendocrine bodies (NEBs) are the only source of GABA in the airway. In addition, my lab found that the neurotrophin 4 (NT4)-dependent innervation of NEBs is required for GABA signaling in early-life allergen-induced mucous hyperplasia. Built upon a paradigm that the neuroendocrine system mediates the communication between the nervous system and endocrine secretion to control important body functions, these preliminary findings implicate an unrecognized role of NEBs in mediating neural control of endocrine GABA secretion in the airway. Here, I hypothesize that the GABAa and GABAß pathways have distinct roles in lung epithelial metaplasia and Muc5ac gene expression after early-life allergen exposure. To address this hypothesis I will: 1) Determine the roles of th GABAa and GABAß pathways in mucous hyperplasia in vivo, 2) Investigate the role of GABA signaling in lung epithelial trans-differentiation ex vivo, and 3) Evaluate the GABAß pathway in Muc5ac gene expression regulation. This proposal will be addressed using specific agonists and antagonists of the GABA pathways in vivo and in vitro. Results of my proposed study may identify new drug targets for the treatment of mucous hyperplasia in asthma.