© 2018 by Eri Hashino. 

RESEARCH

Modeling Human Inner Ear Development 

The primary goal of this study is to clearly define the temporal progression, transcriptome pathways, structural changes and protein-protein interactions during sensory cell differentiation in the human inner ear organoid.  Using a combination of single-cell RNA-seq, ChIP-seq and lineage-tracing analyses, we are determining developmental trajectories of gene expression, lineage specification and transcriptional networks essential for specification of hair cells and sensory neurons in the human inner ear.  Additionally, we are elucidating the transcriptional pathways distinctive for vestibular vs. cochlear specification and determine biochemical and structural properties of hair cells derived from ventralized otic progenitors.  Moreover, we are defining temporal progression of hair cell differentiation (e.g. hair bundle and ribbon synapse development) in human inner ear organoids at both light and electron microscopic levels.   

Modeling Genetic Inner Ear Disorders 

Certain genetic mutations cause congenital or progressive inner ear disorders in humans.  Despite the recent progress in human genetics for identifying syndromic and nonsyndromic genes, little is known about how mutations in these genes contribute to the clinical features of patients with cochlear and/or vestibular dysfunction.  We are generating human embryonic stem cell lines bearing disease-associated mutations using CRISPR/Cas9 genome editing technology, and examine when and how phenotypes manifest themselves using a combination of histological, biochemical and electrophysiological assays.  An additional experiments are being designed to elucidate the mechanisms underlying the pathological defects and test if some of the defects can be rescued by forced expression of exogenous genes. 

Hair Cell Regeneration

Sensory hair cells in the human inner ear, damaged by loud noise, ototoxic drugs or aging, do not regenerate to any clinically relevant degree.  Thus, most forms of hearing loss cannot be cured by currently available treatment regimens.  Establishing means to promote hair cell regeneration has been a prime target area of research in the field, but progress has been hampered due to the lack of reliable human model systems to test potential treatment options before clinical trials.  The goals of this project are to develop an inducible in vitro human model of hair cell degeneration and carry out a chemical screen to identify compounds that have the potential to promote hair cell regeneration in the human inner ear.  Identified compounds will be subjected to modifications and GLP purifications, leading to drug discovery and clinical trials.  Our ultimate goal is to develop a novel pharmacological therapy that can restore hearing through biological regeneration of functional sensory hair cells.