Colorado PROFILES, The Colorado Clinical and Translational Sciences Institute (CCTSI)
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Airway-Central Nervous System Control

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Chronic airway diseases such as bronchial asthma and chronic obstructive bronchitis share the salient features of inflammation, hyperresponsiveness to various inhalants, and airway narrowing. Although these two conditions result in enormous morbidity and social cost, the central nervous system mechanisms involved in airway hyperreactivity remain poorly understood. In the prior funding cycle of this proposal we have characterized the primary neurochemical(s) and receptor subtypes involved in transmission of excitatory inputs from the respiratory tract to the nucleus tractus solitarius (NTS) neurons; from these second order sensory cells to airway-related vagal preganglionic motor neurons (AVPNs); and from AVPNs back down to the airways. As a natural continuation of this work, we now focus on inhibitory pathways that regulate cholinergic drive to the airways. Neuroanatomical studies will define the normal neural circuitry between inhibitory GABAergic, catecholaminergic, or serotonergic cell groups and AVPNs. In these studies, retrograde tracing will be used to define AVPNs projecting to the trachea. Dual or triple labeling immunocytochemistry will be used to simultaneously locate neurotransmitters, their receptors, and AVPNs. Tissues will be examined using light microscopy, confocal microscopy, and electron microscopy. Protein levels will be measured by Western blotting. In physiological studies, we will microinject uptake inhibitors, specific agonists, or antagonists into the rostral nucleus ambiguus (rNA, where AVPNs are abundant), to define the functional roles of specific inhibitory neurotransmitters and their receptors on basal and reflex-induced changes in tracheal tone and airway resistance. Subsequently, we will test the hypothesis that repeated exposure to allergens in sensitized animals induces morphological and physiological changes in central inhibitory influences, resulting in a shift from inhibitory to excitatory transmission. These changes lead to a hyperexcitable state of AVPNs and to airway hyperreactivity. The results of these studies will provide necessary knowledge in the neural control of the airways and will support the development of novel pharmaceutical strategies which target the central nervous system for the treatment of airway disorders.
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