The mechanism of inner ear pressure homeostasis by the endolymphatic sac

点击翻译按钮获取中文摘要

Abstract Hearing and balance loss is prevalent in every population and poses significant challenges to those affected. For many types of hearing and balance loss including Meniere's Disease, Enlarged Vestibular Aqueduct Syndrome, and Pendred Syndrome, the mechanism underlying the disease is currently unknown but is suggested to result from the loss of endolypmh volume and pressure control in the inner ear. Our long-term goal is to understand how the exquisite morphology of the inner ear is created during development and maintained in adults. Here we focus on the role of inner ear fluid pressure regulation by the endolymphatic sac in this process. The endolymphatic sac is a deeply conserved yet mysterious and poorly studied part of the inner ear. It has previously been suggested that the endolymphatic sac absorbs excess endolymph but through an unknown mechanism. Our preliminary data using state of the art timelapse imaging on larval zebrafish reveals that the endolymphatic sac pulses: the lumenal volume slowly increases over 1-3 hours and then rapidly decreases over several minutes. Endolymph pressure is necessary and sufficient for the expansion of the endolymphatic sac, and breaches in the epithelial barrier are necessary and sufficient for its collapse. These breaches occur at a novel cell-cell junction we term “basal lamellar junctions” that seem to act as pressure relief valves. These preliminary data support our central hypothesis that regulated breaches in the epithelial barrier of the endolymphatic sac at specialized pressure relief valves are essential for proper fluid homeostasis in the inner ear; failure of these pressure relief valves causes endolypmh pressure to build up leading to inner ear swelling, death of sensory cells, and unregulated tearing of the otic epithelium called endolymphatic hydrops. We plan to test our central hypothesis using three specific aims: 1) identify the molecular and cellular mechanisms of valve formation; 2) determine the role of the valve in homeostasis of endolymph pressure and composition; and 3) determine the structure and function of the valve across species and developmental stages. Our experimental approach will use functional studies on zebrafish and quail and descriptive studies on mouse and human. Our studies will employ state of the art 3D, timelapse, confocal microscopy and serial section electron microscopy along with genetic, pharmacological, and physical perturbations. At the completion of this project, we will have a deeper understanding of the normal physiology of the endolymphatic sac and how disruptions to this physiology may lead to disease. Better knowledge of pressure homeostasis as well as the small molecule reagents we develop will provide a foundation for development of potential therapeutic interventions for these diseases. We are optimistic that this work will establish a new causal mechanism for inner ear pressure diseases such as Meniere's.