Principal Investigator/Program Director (Last, first, middle): Myers, Allen, C RESEARCH &RELATED Other Project Information 1. * Are Human Subjects Involved? m Yes l No 1.a. If YES to Human Subjects Is the IRB review Pending? m Yes m No IRB Approval Date: Exemption Number: 1 2 3 4 5 6 Human Subject Assurance Number 2. * Are Vertebrate Animals Used? l Yes m No 2.a. If YES to Vertebrate Animals Is the IACUC review Pending? l Yes m No IACUC Approval Date: Animal Welfare Assurance Number A3272-01 3. * Is proprietary/privileged information m Yes l No included in the application? 4.a.* Does this project have an actual or potential impact on m Yes l No the environment? 4.b. If yes, please explain: 4.c. If this project has an actual or potential impact on the environment, has an exemption been authorized or an environmental assessment (EA) or environmental impact statement (EIS) been performed? m Yes m No 4.d. If yes, please explain: 5.a.* Does this project involve activities outside the U.S. or m Yes l No partnership with International Collaborators? 5.b. If yes, identify countries: 5.c. Optional Explanation: 6. * Project Summary/Abstract M-11_Project_Summary.pdf Mime Type: application/octet-stream 7. * Project Narrative M-1_Narrative.pdf Mime Type: application/octet-stream 8. Bibliography &References Cited M-17_Bibliography.pdf Mime Type: application/octet-stream 9. Facilities &Other Resources M-9_Facilities.pdf Mime Type: application/octet-stream 10. Equipment M-12_Equipment.pdf Mime Type: application/octet-stream Tracking Number: Other Information Page 5 OMB Number: 4040-0001 Expiration Date: 04/30/2008 Principal Investigator/Program Director (Last, first, middle): Myers, Allen, C In the lower airways, the activity of airway smooth muscle, microvasculature, and glands and, consequently, air flow to the lungs, is regulated predominantly by the parasympathetic nervous system. Over the past decade, we have demonstrated that airway parasympathetic ganglionic neurons regulate input (preganglionic) from the central nervous system and how this is altered by neighboring nerves or by inflammation. In this proposal, we will address hypotheses related to how neurotrophins, especially nerve growth factor (NGF), regulate the function of adult airway parasympathetic neurons. Neurotrophins, such as NGF, are increased in the inflamed or infected airways and many symptoms of these diseases (hyperactivity, cough, mucous production) may be related to altered or aberrant functions of the airway nervous system as seen in asthma, chronic obstructive pulmonary disease (COPD), and chronic bronchitis. Neurotrophins function during development, particularly as survival factors, but also as factors involved in differentiation and axon growth. However, both the neurotrophins themselves (NGF, BDNF, NT-4/5 and NT-3) and their high affinity receptors (trkA, trkB and trkC) continue to be expressed post-natally indicating that their function goes far beyond their role in development. We propose to study their role in modulating the airway parasympathetic nervous system in adult animals (mice) and in humans. In Specific Aim 1, we will evaluate the mechanisms by which NGF increase synaptic efficacy at airway parasympathetic ganglia;in this aim, we will directly address hypotheses related to NGF-induced changes in synaptic transmission in mouse and human pig bronchial parasympathetic ganglia as well as hypotheses pertaining to the mechanisms by which neurotrophins modulate the action potential. In Aim 2, we'll determine how neurotrophins regulate the anatomy and neurotransmitter phenotype of airway neurons in mouse and human excitatory cholinergic and inhibitory neurons. In this Aim, we will address hypotheses relating to the changes in dendritic structure that occur with chronic exposure to NGF (and potentially, other neurotrophins), and address the hypothesis that neurotrophins can modulate the function of parasympathetic nerves by altering the neurotransmitter(s) they release. Results from these studies will shed new light on the complex pathophysiology of airway diseases such as asthma and COPD and may ultimately determine new therapeutic treatments for these complex diseases. Project Description Page 6