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. The long-term goal of our research is to improve prevention and management of vocal fold disease by identifying and manipulating the manner in which epithelial cell-fibroblast interactions modulate healthy and aberrant mucosal healing following inflammation. In our previous funding period, as a necessary first step to towards achieving our long term goal, we developed a steady source of stable vocal fold epithelial cells to study epithelial cell-fibroblast interactions and established a novel physiologically relevant, three-dimensional biomimetic in vitro vocal fold model of human origin. For the proposed funding period, we will specifically focus on using a unique combination of in vitro and vivo model systems, including those developed in the previous funding period, to further our knowledge of host mediated immune defenses and inflammatory based tissue alterations in the vocal fold mucosa when exposed to defined bacteria species. The overall objective of this proposal is to identify mechanisms by which resident commensal or pathogen bacterial species are identified by vocal folds via specialized receptors and control tissue immune homeostasis while promoting immune responses in the context of steady state and tissue inflammation.
In Specific Aim 1, we will define the role of commensal bacteria in tuning vocal fold immune cells using gnotobiotic methodologies.
In Specific Aim 2, we will identify toll like family receptors (TLR) in vocal fold tissue and novel human vocal fold epithelial cells in steady state and inflammatory conditions. Lastly, in Specific Aim 3, using our physiologically relevant three- dimensional biomimetic model of normal and inflammatory vocal fold mucosa, we will determine relative contribution of resident commensal and pathogenic microbial communities on vocal fold mucosal integrity and function. Taken together, our multidisciplinary exploitation of microbiology, next gen sequencing, and immunology will converge to reform exponentially our understanding of mechanisms of innate immune- microbial interactions in vocal fold inflammatory diseases. 1
STATEMENT Voice disorders affect an estimated 3-9% of Americans yearly and 29% of the population in their lifetime. Chronic laryngitis whose hallmark is mucosal inflammation, contributes to as much as 60-80% of all voice complaints seen in clinical practice. Despite the central role of the immune system in mucosal inflammation, mechanisms specific to vocal fold epithelia and lamina propria have been largely unexplored. In this application, we seek to define host immune mechanisms, whereby providing a novel and fundamental approach for improving our understanding laryngeal mucosal immunity in health and disease.
| Lungova, Vlasta; Verheyden, Jamie M; Sun, Xin et al. (2018) ?-Catenin signaling is essential for mammalian larynx recanalization and the establishment of vocal fold progenitor cells. Development 145: |
| Thibeault, Susan L; Welham, Nathan V (2017) Strategies for advancing laryngeal tissue engineering. Laryngoscope 127:2319-2320 |
| Tang, Sharon S; Mohad, Vidisha; Gowda, Madhu et al. (2017) Insights Into the Role of Collagen in Vocal Fold Health and Disease. J Voice 31:520-527 |
| Erickson-DiRenzo, Elizabeth; Enos, Gabrielle; Thibeault, Susan L (2016) Early Cellular Response to Radiation in Human Vocal Fold Fibroblasts. Ann Otol Rhinol Laryngol 125:425-32 |
| Lungova, Vlasta; Verheyden, Jamie M; Herriges, John et al. (2015) Ontogeny of the mouse vocal fold epithelium. Dev Biol 399:263-82 |
| Erickson-DiRenzo, Elizabeth; Sivasankar, M Preeti; Thibeault, Susan L (2015) Utility of cell viability assays for use with ex vivo vocal fold epithelial tissue. Laryngoscope 125:E180-5 |
| Palencia, Liliana; Das, Amritava; Palecek, Sean P et al. (2015) Epidermal growth factor mediated healing in stem cell-derived vocal fold mucosa. J Surg Res 197:32-8 |
| Leydon, Ciara; Imaizumi, Mitsuyoshi; Yang, David et al. (2014) Structural and functional vocal fold epithelial integrity following injury. Laryngoscope 124:2764-9 |
| Hartley, Naomi A; Thibeault, Susan L (2014) Systemic hydration: relating science to clinical practice in vocal health. J Voice 28:652.e1-652.e20 |
| Leydon, Ciara; Imaizumi, Mitsuyoshi; Bartlett, Rebecca S et al. (2014) Epithelial cells are active participants in vocal fold wound healing: an in vivo animal model of injury. PLoS One 9:e115389 |
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