The larynx is a strategically important organ situated at the crossroads of the upper respiratory and digestive tracts, orchestrating swallowing, breathing, coughing and, in humans, voice. The hallmark of many clinically important laryngeal diseases affecting these critical functions is mucosal inflammation. In other parts of the body, the pathogenesis of mucosal inflammatory disease is intimately linked to local immune responses. Chronic laryngitis is a laryngeal disorder that represents a significant clinical problem. Treat progress for this disease is hampered due to limited understanding of the immunological architecture of the larynx and how it changes with physiological and pathological challenges. There is a comprehensive need for an understanding of the interaction between the laryngeal mucosal immune system and inflammatory challenges if new, targeted, diagnostic and therapeutic avenues for chronic laryngitis are to be fully realized. Mucosal immunity is determined by the interaction between the `immunological triad'of epithelial cells, bacteria, and professional immune cells in the epithelium and underlying lamina propria. The goal of this research program is to ascertain, mechanistic insights for components of the triad, by studying gene and protein expression, through a series of in vivo and in vitro experiments. This innovative proposal will map the immunological, including bacterial, architecture of the normal laryngeal mucosa and examine how it is altered in chronic laryngitis as defined by diffuse smoke, reflux and/or focal polypoid change. This will be correlated with the effects of interventions -- altered flora, tobacco and refluxate -- on an in vitro model. Our overarching, long-term hypothesis is that significant laryngeal mucosal challenges leave distinguishing immunological and bacteriological fingerprints. We hypothesize that such fingerprints can be modeled in vitro and such models used to develop and direct future interventions for the prevention and treatment of inflammatory and even malignant diseases of the larynx.
Our specific aims are 1) to complete the genetic, proteomic immunological map of the laryngeal mucosa in normal persons and those with chronic laryngitis, 2) to map the laryngeal mucosal bacteriome, including quantification of total eubacterial load and the presence and location of specific species, including helicobacter pylori, within the laryngeal mucosa and lamina propria and 3) to use an in vitro model system to determine the contribution of the bacterial flora of the larynx to its immunological architecture, and how this is influenced by key incident challenges. The development of these maps will have a significant impact on the field of laryngology. We anticipate that the mapping data generated in this project will be highly valuable to other scientists and have included a data sharing plan to make our raw data available to the scientific community. 1

Public Health Relevance

STATEMENT The hallmark of many clinically important laryngeal diseases affecting voice, swallowing, breathing and coughing is mucosal inflammation. Chronic laryngitis whose hallmark is mucosal inflammation, contributes to as much as 60-80% of all voice complaints seen in clinical practice. In other parts of the body, the pathogenesis of mucosal inflammatory disease is intimately linked to local immune responses. This project will provide a comprehensive understanding of the interaction between the laryngeal mucosal immune system and inflammatory challenges as considered by the genome, proteome and bacteriome.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC009600-04
Application #
8209244
Study Section
Motor Function, Speech and Rehabilitation Study Section (MFSR)
Program Officer
Shekim, Lana O
Project Start
2009-01-01
Project End
2013-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
4
Fiscal Year
2012
Total Cost
$494,979
Indirect Cost
$113,656
Name
University of Wisconsin Madison
Department
Surgery
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Hartley, Naomi A; Thibeault, Susan L (2014) Systemic hydration: relating science to clinical practice in vocal health. J Voice 28:652.e1-652.e20
Jetté, Marie E; Gaumnitz, Eric A; Birchall, Martin A et al. (2014) Correlation between Reflux and multichannel intraluminal impedance pH monitoring in untreated volunteers. Laryngoscope 124:2345-51
Li, Nicole Y K; Chen, Fei; Dikkers, Frederik G et al. (2014) Dose-dependent effect of mitomycin C on human vocal fold fibroblasts. Head Neck 36:401-10
Jetté, Marie E; Hayer, Supriya D; Thibeault, Susan L (2013) Characterization of human vocal fold fibroblasts derived from chronic scar. Laryngoscope 123:738-45
King, Suzanne N; Chen, Fei; Jette, Marie E et al. (2013) Vocal fold fibroblasts immunoregulate activated macrophage phenotype. Cytokine 61:228-36
Berchtold, Craig M; Coughlin, Adam; Kasper, Zachary et al. (2013) Paracrine potential of fibroblasts exposed to cigarette smoke extract with vascular growth factor induction. Laryngoscope 123:2228-36
Leydon, Ciara; Selekman, Joshua A; Palecek, Sean et al. (2013) Human embryonic stem cell-derived epithelial cells in a novel in vitro model of vocal mucosa. Tissue Eng Part A 19:2233-41
Bartlett, Rebecca S; Heckman, W Wesley; Isenberg, Jason et al. (2012) Genetic characterization of vocal fold lesions: leukoplakia and carcinoma. Laryngoscope 122:336-42
Li, Nicole Y K; Lee, Byung-Joo; Thibeault, Susan L (2012) Temporal and spatial expression of high-mobility group box 1 in surgically injured rat vocal folds. Laryngoscope 122:364-9
Thibeault, S L; Rees, L; Pazmany, L et al. (2009) At the crossroads: mucosal immunology of the larynx. Mucosal Immunol 2:122-8

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