Electronic cigarettes have rapidly gained popularity and have a widened base among adolescents due to their perceived safety over traditional cigarettes. Epidemiological estimates indicate electronic cigarette vapor (ECV) carries a risk for asthma in young people whereas it may be too early to estimate risk for chronic obstructive pulmonary disease (COPD). Traditional cigarette smoke (CS) contributes strongly to COPD and suppresses host defenses increasing susceptibility to infection. Rodent models indicate similar susceptibility due to ECV. How children and adolescents respond to both CS and ECV, relative to adults, remains poorly understood. Airway epithelia form a structural barrier but also secrete numerous proteins into the airway that protect the lung from the environment and form part of the innate mucosal defense. The innate mucosal defense system of the lung is affected by CS and ECV however how dysregulation of these defenses contributes to lung disease is not clear. It is also unclear whether the age at exposure independently contributes to disease. The overarching hypothesis for this project is that ECV modulates the airway epithelial response to environmental stimuli through the effects on innate mucosal defense proteins. We will address the hypothesis through three specific aims in which we will also compare ECV to the more widely studied CS.
In Aim 1 we will determine the effects of ECV in airway epithelial cells from infant, adolescent, and adult nonhuman primates. We will assess the effects of the exposures on the innate mucosal defenses as well as the regulation of inflammation in the epithelia.
In Aim 2 we will examine the effects of changing levels and function of one of the most abundantly expressed innate mucosal defense proteins, SPLUNC1. We will stimulate airway epithelia with molecules that are surrogates for microbial infection and examine the regulation of the response of epithelia by different levels and functional activity of SPLUNC1.
In Aim 3 we will compare the effects of CS and ECV in a mouse model. Within this model we will vary the levels of SPLUNC1 to determine its ability to regulate inflammation during these exposures and following a challenge with a surrogate molecule for bacterial infection. We will further determine if SPLUNC1 function can be rescued following CS and ECV exposure by administration directly to the lungs. SPLUNC1 is a promising candidate as a new class of therapeutics and these experiments will help determine its efficacy. The candidate, Christopher Royer, DVM, PhD, seeks to (1) gain knowledge and practical experience in mechanistic, hypothesis- driven research through pertinent in vitro methods and rodent models and (2) receive mentored training in scientific writing, research program management, and grantsmanship leading to successful application for R01- level research funding. The SERCA K01 will provide protected time to achieve these objectives and the means to secure preliminary data for future grants launching Dr. Royer's independent biomedical research career.

Public Health Relevance

Electronic cigarettes have rapidly gained popularity especially in adolescence presenting a major concern for the potential to cause long lasting lung disease from an early age. Our goal is to determine the age-related disease potential for electronic cigarettes in comparison to traditional cigarettes. Specifically, we seek to understand the exposure effects at the frontline barrier to the environment and determine the efficacy of a novel therapeutic functioning at this interface with the environment.

Agency
National Institute of Health (NIH)
Institute
Office of The Director, National Institutes of Health (OD)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01OD024782-04
Application #
9942516
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Fuchs, Bruce
Project Start
2017-09-15
Project End
2022-06-30
Budget Start
2020-07-01
Budget End
2021-06-30
Support Year
4
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of California Davis
Department
Veterinary Sciences
Type
Primate Centers
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Miller, Lisa A; Royer, Christopher M; Pinkerton, Kent E et al. (2017) Nonhuman Primate Models of Respiratory Disease: Past, Present, and Future. ILAR J 58:269-280