Deafness and balance disorders resulting from the loss of sensory hair cells of the inner ear are a major cause of disability and morbidity in the US. In mammals, the cells of the various sensory epithelia of the inner ear arise embryonically and subsequently do not regenerate if damaged (Rubel et al., 2013). Hearing loss resulting from the death of hair cells in the organ of Corti is thus permanent, and treatments aimed at reversing hearing loss through stimulated regeneration of hair cells are badly needed. However, experimentation on the cells of the inner ear is difficult due to their small number and extreme inaccessibility in the adult. As a result, modern techniques of cell and molecular analysis and drug discovery have been difficult to apply, and aside from prosthetics, treatment options for sensorineural deafness remain few. To overcome these problems, and in pursuit of new treatments for hair cell loss, we have used powerful new ?direct lineage reprogramming? technologies, originally developed for neuron-specific reprogramming (Son et al., 2011; Vierbuchen et al., 2010), to generate hair cell-like cells in vitro, directly from mouse and human somatic cells (fibroblasts and inner ear supporting cells). This advance allows a new range of experimentation into the mechanisms of hair cell differentiation, the development of preclinical models of genetic hearing loss (disease modeling), high-throughput screening for drug discovery related to regeneration and ototoxicity, and the application of gene therapy approaches to the problem of hair cell regeneration.
The Aims of the proposal include: 1) Development of improved reprogramming strategies to induce mouse and human hair cell-like cells. 2) Development of a drug screen for ototoxicity, and an in vitro disease model of genetic hearing loss. 3) A test of reprogramming in a preclinical model of hair cell regeneration/replacement in long-deafened mice.

Public Health Relevance

Deafness and balance disorders resulting from the loss of sensory hair cells of the inner ear are a major cause of disability and morbidity in the US. Hearing loss resulting from the death of hair cells in the ear is permanent, and treatments aimed at reversing hearing loss through stimulated regeneration of hair cells are badly needed. We will apply powerful new ?direct lineage reprogramming? technology to induce sensory hair cell-like cells from more basic cell types. These induced hair cells will be used to develop tools for drug discovery to address the problems of hearing loss, as well as in translational experiments to induce replacement of hair cells in long-deafened animals.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC015530-04
Application #
9709272
Study Section
Auditory System Study Section (AUD)
Program Officer
Freeman, Nancy
Project Start
2016-07-01
Project End
2021-06-30
Budget Start
2019-07-01
Budget End
2020-06-30
Support Year
4
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Southern California
Department
Otolaryngology
Type
Schools of Medicine
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
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