Basic and clinical research over the past decade is shedding new light on the major role played by the nervous system in respiratory pathophysiology, in particular in the ?hypertussivity? associated with chronic unproductive cough, in the ?airways hyperresponsiveness?? associated with of asthma, and in the airway narrowing and secretions associated with COPD. The evidence supports the hypothesis that these hyperactive disorders are in part secondary to dysregulation of vagal afferent C-fibers that comprise some 75% of the nerves within the respiratory tract. This grant aims to advance our understanding of the nature of the inflammatory mediators (autacoids and cytokines) responsible for activating airway C-fibers and the specific ionic mechanisms underlying this activity. This R35 will replace my two active R01 grants: R01 HL137807 ?Mechanisms of Inflammatory Activation of Vagal C-Fibers in the Respiratory Tract? and R01HL122228 ?Control of Airway Sensory Nerve Function by Voltage- Gated Sodium Channel Subtypes.? The R35 funding will allow us to go beyond the aims of the R01 grants that focus on healthy animals, and delve into the mechanisms that lead to the neuroplasticity associated with airway inflammation. In particular, we propose to evaluate the neuroplasticity in the afferent nervous system that accompanies viral infection during early life ?critical periods? with the hypothesis that such infections cause persistent neuroplastic changes. These changes lead to a hyperreactive neurophysiological state that can last into adulthood. This grant will also allow us to continue to advance more user-friendly technologies for studying airway nerves by taking advantage of modern imaging methodologies. These methods will not only serve to advance our own studies, they will also likely be exported to other laboratories interested in visceral neuroscience in general, and airway neuroscience in particular. We will also continue to advance our techniques and studies into the study of human bronchial innervation. Finally, the award will help keep the path paved for continued mentoring of young investigators interested in pursuing airway neuroscience research.
Basic and clinical research over the past decade is shedding new light on the major role played by the nervous system in asthma, COPD, and chronic coughing. This proposal focuses on unraveling the chemical and ionic mechanisms of airway nerve activation and on identifying the specific aspects of airway inflammation, especially during early life that leads to a hyperactive neuronal state in the airways. The findings will increase our understanding of airway biology, and will continue to define new therapeutic targets aimed at reducing the suffering of those with inflammatory airway diseases.