Genetic pathways that contribute to fibrosis in iatrogenic vocal fold scar

PROJECT SUMMARY/ABSTRACT Voice disorders represent a significant healthcare cost in the US, and a notable patient burden on quality of life. Vocal fold scar, which occurs because of injury (iatrogenic) or idiopathically, often results in significant alteration of the voice and is a particularly difficult condition to treat. There is no single treatment modality that is successful for the majority of patients, nor is there a gold standard practice pattern for vocal fold scar management. A key limiting factor in treatment development is insufficient understanding of the activity in gene pathways that lead to the production of molecular components found in fibrotic scar tissue. Broadly, TGF- β (transforming growth factor beta) signaling pathway has been linked to fibrotic phenotypes in stratified squamous epithelial cell environments throughout the body. In vocal folds specifically, downstream genetic effectors of the TGF-β signaling pathway have been implicated in fibrosis in prior studies. The aim of this study is to comprehensively examine the TGF-β pathway and identify the specific transcript-level changes associated with vocal fold scar. To achieve this goal, this proposal is comprised of three study aims: (1) Derive the expression of extracellular matrix components and TGF-β pathway genes in vocal fold scar using an established in vivo rabbit model, (2) Identify specific contributions of TGF-β pathway genes to vocal fold scar by a priori overexpression in primary vocal fold cell lines, (3) Compare expression of TGF-β pathway transcripts from the animal scar model to laryngeal secretion samples from vocal fold scar patients. This proposal represents a significant step to investigate gene pathways that lead to vocal fold scar and marks the first attempt to confirm these pathways in in vivo and in vitro models. As a direct result of this proposal, we will gain a more complex understanding of the genetic influence on vocal fold scar. Thus, the findings have the potential to inform new targets for therapeutic management of this difficult to treat voice condition. As a Ph.D. student in the Department of Communication Science and Disorders, Lizzie Hary is supported by a multidisciplinary collaborative mentorship team of leaders in the fields of speech-language pathology, laryngology, comparative genetics and bioinformatics, and molecular biology. As a predoctoral research fellow, her training will focus on skills needed to develop a high-quality biomedical research program, including (1) applied molecular approaches to study cellular repair, (2) analysis and interpretation of sequencing datasets, (3) synthesis and dissemination of translational data, and training in human subject design, (4) career skills in leadership and professional development. The support for this proposal will serve as the foundation for her goal of becoming a successful independent researcher in voice science.