Molecular regulation of fluid pressure homeostasis in the inner ear
Project Summary
A significant portion of hearing and balance disorders are caused by the unregulated accumulation of
endolymph fluid and pressure within the inner ear. A key challenge in treating these diseases of elevated
endolymph pressure is identifying new strategies to regain pressure homeostasis. We previously discovered a
tissue-scale pressure relief valve in the epithelial tissue of the endolymphatic sac whose behavior is consistent
with long observed physiologies that lacked explanations. Despite its importance in maintaining an internal
environment within the ear, the molecular and cellular mechanisms by which the endolymphatic sac forms and
functions remain unclear. The long-term goal of this research is to define how molecular signals during
development and during homeostasis control the pressure relief valve's setpoint. Using a combination of
advanced live imaging, genetics, and cell and molecular biological technologies like genome editing, we study
these systemic processes in zebrafish embryos and larvae whose inner ears are optically accessible in the
living animal instead of buried within the temporal bone as in mice and humans. Our prior generation of a
single-cell gene expression atlas of the zebrafish inner ear identified molecular leads of signaling pathways in
the endolymphatic sac. Synthesis with past work motivates our central hypothesis which posits that cells within
the endolymphatic duct maintain a strong adhesive interaction, while adhesion strength at distinct subsets of
cell-cell interfaces in the endolymphatic sac is reduced by adhesion protein turnover. This regulatory
mechanism allows these interfaces to temporarily separate, facilitating the release of excessive pressure. We
will pursue how the integration of molecular signals regulates these local cell behaviors to determine the
pressure setpoint within the entire inner ear. First, we will determine how regulation of spatiotemporal
differences in Wnt signaling regulate turnover rates of cell-cell adhesion complexes in subregions of the
endolymphatic duct and sac. Second, we will determine the molecular responses in the endolymphatic sac that
are regulated by vasopressin and how these responses integrate into physiological circuits. Third, we will
determine how mechanical and calcium signals contribute to tissue contractions in the endolymphatic sac to
regulate resistance to stretch. These studies will uncover regulatory mechanisms that determine the inner ear's
pressure setpoint that are essential for our ability to sense sound for hearing and body acceleration for
balance.