Severe asthma afflicts about 10% of asthma patients, but utilizes 30 to 50% asthma-associated healthcare costs. It is imperative to understand the mechanisms by which severe asthma in particular acute exacerbation develops. To improve the understanding of severe asthma and to develop better treatments, for the last 14 years, NIH/NHLBI has funded the Severe Asthma Research Program (SARP), the world's most comprehensive study of adults and children with severe asthma that are currently performed at seven leading asthma research sites in the US. The current SARP (SARP3) has started collecting upper and lower airway samples to study severe asthma pathobiology. This offers an unprecedented opportunity to further our understanding of natural history of asthma, disease progression and new therapeutic interventions. However, SARP3 protocols do not include the collection of minimally invasive nasal airway epithelial cells, an approach that can be repeated longitudinally to study asthma pathogenesis. Thus, we propose a time-sensitive study by using nasal airway epithelial cells to determine the role of a novel host defense protein SPLUNC1 in severe asthma. Short palate, lung, and nasal epithelium clone 1 (SPLUNC1) is a secretory protein from large airway (nasal, tracheal and bronchial) epithelial cells and is abundant in the epithelial lining fluid of healthy individuals. Through collaboration with SARP investigators, we identified SPLUNC1 as one of the most significantly decreased proteins in bronchoalveolar lavage fluid samples from severe asthmatics. We have found that SPLUNC1 exerts host defense functions against human rhinoviruses and bacteria involved in asthma exacerbations - a leading cause of morbidity, mortality and health care costs in asthma. We discovered SPLUNC1-deficient mice have exaggerated airway allergic inflammation following allergen challenges (e.g., eosinophils and mucus, relevant to asthma exacerbations). Moreover, transgenic over-expression of human SPLUNC1 in mouse airways attenuates allergen-induced eosinophilic inflammation. However, the role of SPLUNC1 in human severe asthma is unclear. We hypothesize that down-regulation of SPLUNC1 in asthmatic airways increases rhinovirus infection and associated asthma exacerbations contributing to asthma severity. In continuing collaboration with SARP and its data coordination center, we will define the role of SPLUNC1 in severe asthma phenotypes. Furthermore, we will team up with 4 SARP sites to collect brushed live nasal airway epithelial cells from asthmatic children and adults during asthma exacerbations to determine if lower baseline SPLUNC1 levels predispose the patients to rhinovirus infection and asthma exacerbations. Finally, we will mechanistically determine SPLUNC1's anti-viral and anti-inflammatory functions that are critical to the prevention of asthma exacerbations. Successful completion of this time-sensitive ancillary R01 proposal will guide use of SPLUNC1 as a biomarker and a new therapy to prevent or treat acute asthma exacerbations.

Public Health Relevance

Severe asthma impacts a minority of asthmatics, but accounts for a majority of the healthcare costs. The basic mechanisms of severe asthma in particular 'acute exacerbations' are poorly understood, which hinders the development of more effective treatments. Our proposed studies will use minimally invasive nasal airway epithelium sampling procedures, to investigate the role of a novel host defense protein SPLUNC1 in severe asthma. These studies will determine how SPLUNC1 affects severe asthma patients at the baseline (stable status), and in particular, when the patients suffer from disease worsening (acute exacerbations). Our research findings are expected to provide a minimally invasive approach that predicts asthma severity, and to suggest SPLUNC1 as a potential therapy that attenuates acute asthma exacerbations. (End of Abstract)

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
3R01HL125128-01A1S1
Application #
9174103
Study Section
Special Emphasis Panel (ZHL1-CSR-I (O1))
Program Officer
Noel, Patricia
Project Start
2015-07-15
Project End
2019-04-30
Budget Start
2016-01-07
Budget End
2016-04-30
Support Year
1
Fiscal Year
2016
Total Cost
$44,401
Indirect Cost
$8,155
Name
University of Pittsburgh
Department
Public Health & Prev Medicine
Type
Other Domestic Higher Education
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Caves, Elizabeth A; Butch, Rachel M; Cook, Sarah A et al. (2017) Latent Membrane Protein 1 Is a Novel Determinant of Epstein-Barr Virus Genome Persistence and Reactivation. mSphere 2:
Chen, Chen; Mangoni, Maria Luisa; Di, Y Peter (2017) In vivo therapeutic efficacy of frog skin-derived peptides against Pseudomonas aeruginosa-induced pulmonary infection. Sci Rep 7:8548
Chen, Yin; Vasquez, Monica M; Zhu, Lingxiang et al. (2017) Effects of Retinoids on Augmentation of Club Cell Secretory Protein. Am J Respir Crit Care Med 196:928-931
Chen, C; Deslouches, B; Montelaro, R C et al. (2017) Enhanced efficacy of the engineered antimicrobial peptide WLBU2 via direct airway delivery in a murine model of Pseudomonas aeruginosa pneumonia. Clin Microbiol Infect :
Deslouches, Berthony; Di, Y Peter (2017) Antimicrobial peptides with selective antitumor mechanisms: prospect for anticancer applications. Oncotarget 8:46635-46651
Ngo, Kevin; Pohl, Pedro; Wang, Dong et al. (2017) ADAMTS5 Deficiency Protects Mice From Chronic Tobacco Smoking-induced Intervertebral Disc Degeneration. Spine (Phila Pa 1976) 42:1521-1528
Jiang, Di; Matsuda, Jennifer; Berman, Reena et al. (2017) A novel mouse model of conditional IRAK-M deficiency in myeloid cells: application in lung Pseudomonas aeruginosa infection. Innate Immun 23:206-215
Walton, William G; Ahmad, Saira; Little, Michael S et al. (2016) Structural Features Essential to the Antimicrobial Functions of Human SPLUNC1. Biochemistry 55:2979-91
Berman, Reena; Jiang, Di; Wu, Qun et al. (2016) MUC18 Regulates Lung Rhinovirus Infection and Inflammation. PLoS One 11:e0163927
Cappiello, Floriana; Di Grazia, Antonio; Segev-Zarko, Li-Av et al. (2016) Esculentin-1a-Derived Peptides Promote Clearance of Pseudomonas aeruginosa Internalized in Bronchial Cells of Cystic Fibrosis Patients and Lung Cell Migration: Biochemical Properties and a Plausible Mode of Action. Antimicrob Agents Chemother 60:7252-7262

Showing the most recent 10 out of 14 publications