Asthma, COPD, and chronic cough, as with other visceral inflammatory diseases, are characterized by an over-excited sensory nervous system. When airway sensory nerves are dysregulated by inflammation it can lead to excessive coughing, dyspnea, changes in breathing pattern, and reflex bronchospasm and secretions that can threaten lung function. Our long-range goal is to determine the ion channels and mechanisms that underlie the excitability of each of the sensory nerve subtypes in the airways. The present proposal focuses on voltage-gated sodium channels (NaVs). NaV are perhaps the most important ion channels regulating nerve activity as they are required for action potential generation and conduction, and are also involved in setting the threshold for nerve activation. There are nine NaV subtypes termed NaV1.1-1.9. This renewal proposal builds on our seminal observations and strong progress since the original application. We now know that the three nociceptor subtypes in the airways express almost exclusively NaV 1.7, NaV 1.8, and NaV 1.9. These channels are not present in skeletal or cardiac muscle and are very modestly expressed in the central nervous system. This renders them ideal targets for drugs aimed at normalizing an overactive airway sensory nervous system. We have completed an extensive functional analysis on the role of NaV1.7 and 1.8 in regulating each of three distinct nociceptor subtypes at the level of their terminals within the airways.
In AIM I we will turn our attention to the mechanisms by which NaV1.9 regulates the excitability of these nerves.
In AIM 2 we will evaluate genetically and functionally the NaV subtypes expressed in non-nociceptive RAR/SAR stretch receptive fibers.
In AIM 3 we will will begin our evaluation of the role of NaV1.8 and 1.9 in the airways hyperexcitability that is associated with respiratory viral infections.
In AIM 4 we will use our newly developed extrinsically innervated isolated human bronchus to evaluate, for the first time, the translatability of the major findings we obtain in laboratory animals to the human condition. We anticipate that this work will provide a conceptual and rational framework with which to base future clinical studies with selective NaV1 blocking drugs that can be applied directly to the sensory terminals in the airways with topical inhaled delivery methods.
Inappropriate activation of vagal sensory nerves in the airways can lead to symptoms of airway diseases including severe reflex bronchospasm, excessive secretions, nonproductive coughing, and sensations of breathlessness. The long-range goal of this proposal is to develop a better understanding of the mechanisms that regulate the activity of these vagal sensory nerves and to identify therapeutic strategies aimed at limiting their activation. !
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