Michael Hoa, M.D., Otolaryngology Surgeon-Scientist
Research Statement
The Auditory Development and Restoration Program, which is part of the NIDCD Otolaryngology Surgeon-Scientist Program (OSSP), investigates the development and function of adult cochlear cell types and their relationship to disorders of hearing instability. The long-term goal of the lab is to identify therapeutic targets and novel treatments for hearing instability disorders, including Ménière’s disease, autoimmune inner ear disease, sudden sensorineural hearing loss, and enlarged vestibular aqueduct syndrome. We ultimately seek to identify ways to enable hearing restoration in the adult inner ear.
Human diseases with hearing instability and progressive hearing loss have few, if any, effective treatments. Included in hearing instability disorder presentations are patients who experience sudden changes in hearing (including, but not limited to, sudden sensorineural hearing loss) as well as patients who experience hearing fluctuation (including, but not limited to, autoimmune inner ear disease, Ménière’s disease, and enlarged vestibular aqueduct syndrome). Human temporal bone studies demonstrate endolymphatic hydrops, which is an expansion of the endolymph-containing scala media of the cochlea, in some patients with hearing instability disorders, which suggests an underlying issue related to cochlear ionic homeostasis, but the underlying mechanisms remain poorly characterized.
The lateral wall of the cochlea, including the stria vascularis, is essential for regulating ion homeostasis and generating the endocochlear potential (EP), which is essential for proper hair cell function and hearing. With this in mind, the lab seeks to: (1) use our understanding of stria vascularis development, structure, and function to identify mechanisms that connect dysfunctional inner ear ion homeostasis to hearing loss and hearing instability; and (2) identify therapeutic strategies to treat strial-based hearing loss and hearing instability.
Current projects in the lab include (1) identification of phenomic features that distinguish patients with hearing instability disorders through deep phenotyping, and (2) investigating the underlying mechanisms that connect dysfunctional ion homeostasis with hearing instability.
In the lab, we use the mouse to study stria vascularis function in the cochlear lateral wall. The stria vascularis is composed of three cell layers consisting of marginal cells on the luminal surface, intermediate cells in the central layer, and basal cells in the basolateral layer. The intermediate cell is fundamental to the generation of the EP, but it is the close interaction between the three cell types that results in a fully functional organ.
Stria vascularis cellular heterogeneity and organization
(A): Schematic of the stria vascularis (SV) and its relationship to structures in the cochlea. The SV is composed of three layers of cells and is responsible for generating the +80 mV endocochlear potential (EP) and the high potassium concentration in the endolymph-containing scala media. The relationship between the marginal, intermediate, and basal cells are demonstrated with the marginal extending basolateral projections to interdigitate with intermediate cells, which have bidirectional cellular projections that interdigitate with both marginal and basal cells. In addition to these cell types, other cell types, including spindle cells (yellow), endothelial cells, pericytes, and macrophages (not shown) are present in the SV.
(B): Cross-section of the SV in a postnatal day 30 (P30) mouse immunostained with anti-SLC12A2 (marginal cells, red), anti-KCNJ10 (intermediate cells, green), and DAPI (4′,6-diamidino-2-phenylindole) for nuclei. Notice the interdigitation of cellular processes from both intermediate and marginal cells. Scale bar is 20 μm.
Source: Korrapati S, Taukulis I, Olszewski R, Pyle M, Gu S, Singh R, Griffiths C, Martin D, Boger E, Morell J, Hoa M. Single cell and single cell nucleus RNA-Seq reveal cellular heterogeneity and homeostatic regulatory networks in adult mouse stria vascularis. Front Mol Neurosci 2019 Dec 20.
doi: 10.3389/fnmol.2019.00316. eCollection 2019.
To investigate these interactions, the lab uses a combination of single-cell mRNA-sequencing, bioinformatics, fluorescent-activated cell sorting (FACS), adult and perinatal immunohistochemistry, confocal microscopy, animal auditory function testing, pharmacology, and molecular biology techniques.
Clinically, our program is interested in addressing the basis for hearing instability disorders (i.e. Ménière’s disease, sudden hearing loss, and autoimmune inner ear disease) and identifying potential novel therapies for these disorders. To this end, we have initiated a clinical protocol to perform deep phenotyping of patients with hearing instability disorders.
Lab staff as of October 2020 (L-R): Rafal T. Olszwski, Ph.D., Ian Taukulis, B.S., Shoujun Gu, Ph.D., Michael Hoa, M.D.