ABSTRACT
The larynx requires protection from the ~25 million inhaled insults encountered daily during fulfillment of its
normal functions including breathing, coughing, swallowing, and in humans, voice production. An epithelium
forms a critical first protective barrier on the surface of the larynx. Under normal conditions, the epithelium
relies on homeostatic regenerative mechanisms. The basal cell (BC) layer of the epithelium is believed to
represent a reservoir of progenitor cells for the formation and regeneration of differentiated epithelium.
However, pathological changes, or remodeling, occurs in the composition and organization of the laryngeal
epithelium in response to inhaled insults, notably cigarette smoke (CS). Remodeling affects the ability of the
epithelium to function as an effective barrier and predisposes the tissue to disease development. Despite the
prevalence and likely importance of epithelial remodeling in CS-induced laryngeal disease, its etiology is poorly
understood. This is due to a lack of basic knowledge of the mechanisms which dictate laryngeal epithelial
homeostatic regeneration and permanent tissue remodeling linked to CS. Specifically, little is known about the
biology of the BC population in normal epithelial homeostasis, injured, or diseased conditions. A paucity of
research on laryngeal BC biology serves as a major barrier in the development of therapies to prevent and
treat CS-diseased vocal folds. To address this unmet need, we propose to test the central hypothesis that BC
are critical to the formation and maintenance of normal laryngeal epithelium and CS-induced alterations in BC
biology are associated with epithelial remodeling and human disease development. We will test this hypothesis
using a normal mouse model (AIM 1) and in vivo and in vitro models of CS exposure (AIM 2) to study laryngeal
BC properties in differentiated epithelium, primary culture, and physiologically relevant three-dimensional
epithelial cell culture systems. We also propose to evaluate how our in vivo and in vitro findings in mice relate
to the human condition by evaluating the biology of BC in human laryngeal specimens from patients with
Reinke’s edema, a common CS-induced laryngeal disease (AIM 3). Completion of these aims will demonstrate
that BC have a central and irreplaceable role in laryngeal epithelial biology- they function as progenitor cells for
normal epithelium and alterations in BC biology are implicated in disease development. Findings will have
significant theoretical and clinical impact and will provide novel new insights into the mechanism underlying
laryngeal and vocal fold epithelial regeneration. Targeting specific biologic pathways that mediate CS-induced
derangements in BC biology may represent innovative therapeutic targets to prevent development and
progression of CS- and other smoke-mediated voice disorders.
