Voice disorders affect approximately 7.5 million people in the United States 1. These disorders are debilitating and can lead to social withdrawal, loss of income, long-term disability, and significant socioemotional consequences. It is generally believed that these disorders can be prevented through efficient use of the vocal mechanism, and that phonotrauma is a major cause of vocal fold lesions. Although histological and physiological comparisons are often made between the vocal folds and other mobile tissues in the body, the cellular response to repeated cycles of trauma and inflammation secondary to phonation are unique to this specialized connective tissue. Unfortunately, there exists a critical shortage of information on the cellular and molecular events underlying acute phonotrauma, an area which has been acknowledged as a compelling public health need by the National Institute on Deafness and other Communication Disorders. Improved understanding of these events is critical to the development and testing of pharmacologic agents, behavioral strategies, and treatments for rehabilitation and prevention of human voice disorders. The identification of mechanisms involved in protection of the vocal fold has important therapeutic implications and will allow for the direct testing of some of the most widely accepted hypotheses for which there are currently very limited empirical data to support. To address this significant need, our laboratory has developed a novel in-vivo rabbit phonation model to investigate the cellular and molecular mechanisms underlying acute phonotrauma. The work proposed in this application builds on a programmatic series of investigations, which provided the necessary pilot data and the development of several key hypotheses to be tested in the current proposal. Our preliminary studies have revealed alterations in inflammatory signaling in the vocal folds following raised intensity phonation. These transcript level changes are associated with changes to epithelial surface morphology, evidence of microhole formation, and dilatation of epithelial tight junctions. These investigations have led to an overarching hypothesis that the downregulation of tight junction proteins, alteration of the paracellular pathway, and increased paracellular permeability, compromises epithelial barrier function and exposes the underlying lamina propria to inflammation and further injury. If our overarching hypothesis is supported it will implicate barrier dysfunction as an early event in mucosal inflammation, and provide support for the maintenance of epithelial barrier integrity as an approach for protection against phonation related injury. We anticipate that this line of programmatic inquiry will ultimately translate into a research program focusing on the design and testing of pharmacologic agents for improving epithelial barrier function in future human trials.
Voice disorders have a significant impact on communication and overall quality of life. The development of improved treatments for voice disorders depends on a better understanding of the mechanisms involved in acute phonotrauma. The long-term goal of this research is to develop more effective treatments for the millions of patients with voice disorders in the United States.
| Mizuta, Masanobu; Kurita, Takashi; Kimball, Emily E et al. (2017) Structurally and functionally characterized in vitro model of rabbit vocal fold epithelium. Tissue Cell 49:427-434 |
| Novaleski, Carolyn K; Carter, Bruce D; Sivasankar, M Preeti et al. (2017) Apoptosis and Vocal Fold Disease: Clinically Relevant Implications of Epithelial Cell Death. J Speech Lang Hear Res 60:1264-1272 |
| Novaleski, Carolyn K; Kojima, Tsuyoshi; Chang, Siyuan et al. (2016) Nonstimulated rabbit phonation model: Cricothyroid approximation. Laryngoscope 126:1589-94 |
| Chang, Siyuan; Novaleski, Carolyn K; Kojima, Tsuyoshi et al. (2016) Subject-Specific Computational Modeling of Evoked Rabbit Phonation. J Biomech Eng 138: |
| Novaleski, Carolyn K; Mizuta, Masanobu; Rousseau, Bernard (2016) Evaluation of Dying Vocal Fold Epithelial Cells by Ultrastructural Features and TUNEL Method. Cells Tissues Organs 202:355-368 |
| Novaleski, Carolyn K; Kimball, Emily E; Mizuta, Masanobu et al. (2016) Acute exposure to vibration is an apoptosis-inducing stimulus in the vocal fold epithelium. Tissue Cell 48:407-16 |
| Kojima, Tsuyoshi; Valenzuela, Carla V; Novaleski, Carolyn K et al. (2014) Effects of phonation time and magnitude dose on vocal fold epithelial genes, barrier integrity, and function. Laryngoscope 124:2770-8 |
| Kojima, Tsuyoshi; Van Deusen, Mark; Jerome, W Gray et al. (2014) Quantification of acute vocal fold epithelial surface damage with increasing time and magnitude doses of vibration exposure. PLoS One 9:e91615 |
| Tian, Fang-Bao; Dai, Hu; Luo, Haoxiang et al. (2014) Fluid-structure interaction involving large deformations: 3D simulations and applications to biological systems. J Comput Phys 258: |
| Kojima, Tsuyoshi; Mitchell, Joshua R; Garrett, C Gaelyn et al. (2014) Recovery of vibratory function after vocal fold microflap in a rabbit model. Laryngoscope 124:481-6 |
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