PROJECT SUMMARY/ABSTRACT The lifetime prevalence of voice disorders in the adult United States population is 30% with point prevalence rates of 6.6% to 7.5%1,2. Point prevalence and census estimates suggest that nearly 20-23 million adults may experience dysphonia annually, with the cost of treatment and lost wages approaching $13 billion dollars3. These annual direct costs are comparable to those associated with chronic obstructive pulmonary disease, asthma, diabetes, and allergic rhinitis3. Thus, improving the care of patients with voice disorders remains a significant public health need. To address this need, over the last 17 years, our research program has initiated systematic studies in the understanding of the cellular and molecular pathophysiology underlying vocal fold tissue changes. Our studies to date have provided critical new insights into the cellular and molecular sequalae regulating vocal fold permeability. Over the last 5 years, we have focused our studies on the safety and efficacy of pharmacological treatments for voice disorders. Our preliminary data have revealed mechanisms regulating permeability of the vocal fold epithelial barrier from a class of steroid hormones ubiquitously found in most cells in the human body. Beyond the anti-inflammatory actions of these glucocorticoids, emerging evidence in our laboratory supports a role for glucocorticoids in the regulation of the vocal fold paracellular pathway. These preliminary data have led to an overarching hypothesis that vocal fold epithelial permeability can be selectively regulated using pharmacological approaches that target the paracellular pathway. This novel treatment concept provides exciting new possibilities in the management of vocal fold disease by providing pharmacologic access to the subepithelial space–and a means for transepithelial delivery of commonly available fillers and biomaterials to the vocal folds. Over the next five years, we will converge our next series of studies on the selective regulation of vocal fold epithelial permeability using a combination of in vitro and in vivo experiments. The current R01 builds on a programmatic series of investigations which have provided the necessary preliminary data to support selective permeability of the vocal fold paracellular pathway. The goal of this R01 proposal is to empirically quantify the effects of methylprednisolone on selective regulation of the vocal fold paracellular pathway. These pre-clinical studies are necessary to provide indications for use, safety, and the demonstration of therapeutic efficacy prior to human trials. The specific deliverable upon project completion will be the preliminary studies necessary for rigorous testing in phase I/II/III human trials.