The goal of this project is to determine the role of neurotrophins in the regulation of neuronal responses that lead to asthma-like symptoms induced by ozone exposure. Neurotrophins, such as nerve growth factor [NGF) and brain-derived neurotrophic factor (BDNF), maintain and regulate neuropeptide and neurotransmitter expression in neurons. Recent studies have shown that neuropeptides and neurotransmitters synthesized and released from airway neurons are important in modulating airway responses to inhaled irritants. The studies in this proposal focus on neurons of airway ganglia. These neurons form the final pathway for both excitatory cholinergic and inhibitory non-adrenergic, non-cholinergic (iNANC) innervation of airway smooth muscle and produce neuropeptides and neurotransmitters that are important regulators of airway and vascular smooth muscle tone, mucous secretion, and mucosal inflammation in the airways. Our studies have demonstrated that NGF enhances substance P (SP) levels in neurons of airway ganglia and increases SP-innervation of cholinergic neurons within the airway. SP enhances airway cholinergic tone by increasing acetylcholine release so regulation of SP synthesis in airway neurons may be important in modulating cholinergic airway responses. Conversely, smooth muscle relaxant mechanisms mediated through iNANC airway nerves may be attenuated through similar neurotrophin signaling pathways. Together, enhanced cholinergic and diminished iNANC influences would lead to airway hyperresponsiveness, as well as increased mucous secretion and airway inflammation. Additional studies are needed to validate hypothesis and elucidate the mechanisms of neurotrophins regulation of cholinergic and iNANC neural pathways of airway neurons. The overall hypothesis of the project is that airway neural responses to inhaled irritants like ozone are mediated through the release of neurotrophins acting on neurotrophin receptors which regulate neurotransmitter or neuropeptide expression in airway neurons.
The specific aims are to: 1) demonstrate that ozone exposure increases neurotrophin synthesis and release by airway epithelium and neurotrophin receptor and NK1 receptor expression in airway neurons; 2) determine the direct effects of neurotrophins on cholinergic, iNANC and SP-containing neurons and neurotrophin and NK1 receptors in airway ganglia; 3) demonstrate that ozone-induced phenotypic changes in airway neurons result from the actions of neurotrophins. Control of neurotransmitter or neuropeptide production in airway neurons may be critical in airway defensive responses to inhaled irritants, and neurotrophins may contribute to airway hyperresponsiveness and inflammation during asthma exacerbations precipitated by the inhalation of airway irritants and allergens. ? ? ?
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