Mechanisms of voice disorders associated with vocal fold atrophy

ABSTRACT Clinically, atrophy of the intrinsic laryngeal musculature is poorly defined likely related to limited understanding of fundamental biological processes underlying this complex, aberrant tissue phenotype. This lack of insight underlies suboptimal therapeutic strategies for these challenging patients. In addition to fundamental investigation regarding this phenotype, we hypothesize that initiation and maintenance of atrophy of the intrinsic laryngeal musculature is related to signaling events in the mucosa. Specifically, our laboratory elucidated the role of TGF-β signaling with an emphasis on therapeutic strategies targeting the SMAD family of signaling proteins in the vocal fold lamina propria. SMADs, however, also mediate muscle atrophy in other systems, specifically through regulation of atrogenes and myostatin, a member of the TGF-β superfamily. We hypothesize that the inherent response to injury in the lamina propria elicits and/or enhances an atrophic in the muscle. This concept is inherently innovative in that it refutes clinical dogma suggesting the vocal fold mucosa and muscle of the vocal folds operate as wholly separate and distinct entities. In that regard, we propose to interrogate fundamental and functional laryngeal muscle outcomes of recurrent laryngeal nerve injury-mediated thyroarytenoid atrophy in the context of both acute and chronic mucosal injury. In addition, we seek to interrogate key biochemical relationships and interactions between multiple cell types from the vocal folds to provide foundational insight into processes underling atrophy. And finally, we seek to provide preliminary data related to therapeutic strategies to prevent/treat laryngeal muscle atrophy targeting SMAD signaling. Ultimately, these data represent substantive contributions to the literature and are foundational for the development of novel treatment strategies for millions of patients with disability related to voice disorders and laryngeal disease.