Exaggerated airway smooth muscle (ASM) contraction and airway narrowing are hallmark traits of asthma. Contraction of ASM is predominantly regulated by the nervous system. In airway diseases such as asthma, inflammation causes neural regulation of ASM to become defective, thus promoting hypercontraction. We recently generated a novel porcine model of a chronic airway disease (cystic fibrosis, CF), and discovered that newborn CF pigs display hypercontracted ASM in the absence of airway infection and inflammation. Thus, the mechanism of ASM hypercontraction in CF remains unknown. In the current application, the candidate hypothesizes that defective neural regulation of ASM causes hypercontraction independent of airway inflammation. She hypothesizes this based upon her work indicating that there are several novel nervous system phenotypes in newborn pigs with CF. These include reduced axon density, decreased innervation of the airway, and decreased nerve function. The candidate proposes to: 1) determine whether inhibitory neural control (pro-relaxation) of ASM is defective in CF pigs; and 2) investigate whether blocking pro-contractile neural input ameliorates ASM hypercontraction in CF pigs. The candidate's long-term career goal is to become a recognized leader in neuroscience and airway disease research. She plans to advance both fields by examining neural regulation of ASM using porcine models. The selection of the porcine model is particularly relevant because the airway anatomy and physiology, as well as the nervous system, more closely resemble humans than traditional rodent models. In the current K99/R00 application, the candidate will gain intellectual, professional and technical skills that will allo her to become an independent and successful investigator specializing in neural regulation of ASM. During the mentored phase, she will learn ASM biology, lung slice culturing, Ca2+ imaging, morphometry, and whole animal pulmonary mechanics using flexiVent. She has created an exceptional mentoring team and training plan to ensure she learns these skills. In addition, the candidate will give formal presentations at Mayo Clinic, attend the American Asthma Foundation Funding Breakthrough Research Annual Meeting of Awardees, review manuscripts for American Journal of Respiratory Cell, serve as a group leader for a medical students Problem-Based Learning course, and attain skills important for managing budgets. The candidate will utilize these skills during her independent phase to investigate neural regulation of ASM in acid-induced airway injury. This topic is highly significant as acidification f the airway occurs in asthma and acidic pH potently activates axons innervating the airway. Hence, the candidate has an unprecedented opportunity to elucidate neural mechanisms involved in ASM hypercontraction using models with direct relevance to human disease. In summary, this award will train the candidate to become a leader in neuroscience and airway disease research, thereby advancing the field and enhancing the lives of people living with airway disease.

Public Health Relevance

Exaggerated airway smooth muscle (ASM) contraction and airway narrowing are common in asthma. In the current proposal, neural regulation of ASM in airway disease is investigated using novel porcine models. Completion of this project will provide new insight into neural mechanisms underlying ASM hypercontraction and thus potential therapeutic targets for treating obstructive airway diseases like asthma.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Transition Award (R00)
Project #
4R00HL119560-03
Application #
9306258
Study Section
Special Emphasis Panel (NSS)
Program Officer
Tigno, Xenia
Project Start
2014-05-01
Project End
2019-07-31
Budget Start
2016-09-01
Budget End
2017-07-31
Support Year
3
Fiscal Year
2016
Total Cost
$249,000
Indirect Cost
$65,065
Name
University of Florida
Department
Physiology
Type
Schools of Veterinary Medicine
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611
Atanasova, Kalina R; Reznikov, Leah R (2018) Neuropeptides in asthma, chronic obstructive pulmonary disease and cystic fibrosis. Respir Res 19:149
Jiron, Jessica M; Mendieta Calle, Jorge L; Castillo, Evelyn J et al. (2018) Comparison of Isoflurane, Ketamine- Dexmedetomidine, and Ketamine-Xylazine for General Anesthesia during Oral Procedures in Rice Rats (Oryzomys palustris). J Am Assoc Lab Anim Sci :
Reznikov, Leah R; Meyerholz, David K; Abou Alaiwa, Mahmoud et al. (2018) The vagal ganglia transcriptome identifies candidate therapeutics for airway hyperreactivity. Am J Physiol Lung Cell Mol Physiol 315:L133-L148
Meyerholz, David K; Beck, Amanda P; Goeken, J Adam et al. (2018) Glycogen depletion can increase the specificity of mucin detection in airway tissues. BMC Res Notes 11:763
Reznikov, Leah R; Meyerholz, David K; Kuan, Shin-Ping et al. (2018) Solitary Cholinergic Stimulation Induces Airway Hyperreactivity and Transcription of Distinct Pro-inflammatory Pathways. Lung 196:219-229
Meyerholz, David K; Reznikov, Leah R (2017) Simple and reproducible approaches for the collection of select porcine ganglia. J Neurosci Methods 289:93-98
Reznikov, Leah R (2017) Cystic Fibrosis and the Nervous System. Chest 151:1147-1155
Reznikov, Leah R; Meyerholz, David K; Adam, Ryan J et al. (2016) Acid-Sensing Ion Channel 1a Contributes to Airway Hyperreactivity in Mice. PLoS One 11:e0166089