This research involves the biological approach to the treatment of hearing loss. It is designed to investigate the mechanisms involved in mammalian hair cell regeneration. The proposed experiments build upon the observation that global expression of the Atoh1 gene in cochlear cells is sufficient for hair cell genesis. This proposal will test the hypothesis that specific populations of cochlear supporting cells are able to differentiate into hair cells. To accomplish this, Atoh1 will be expressed 1) in a dose-dependent manner, and 2) specifically in the cochlear supporting cells that reside directly beneath the hair cells. The basic experimental protocol will be as follows. Cultured murine organs of Corti will be electroporated with an inducible form of Atoh1. Atoh1 expression will be limited to the supporting cells directly beneath the hair cells because it will be placed under the regulatory control of the GFAP promoter (selectively expressed in the inner phalangeal, inner border, pillar and Dieters'cells) and GLAST promoter (inner border and inner phalangeal cell). Next, hair cells will be killed and then Atoh1 will be upregulated in these specific supporting cells. The ability for these specific supporting cell types to develop into hair cells will be observed using time lapse video microscopy, electron microscopy, and immunohistochemical expression of hair cell specific markers such as myosin 7a. Relevance: The long-term goal of this research is to treat hearing loss with more effective therapies than provided by hearing aids or cochlear implants. Specifically, this research is designed to investigate the basic mechanisms by which the auditory sensory cells, or hair cells, can regenerate in mammals. The overall hypothesis is that replacement of lost hair cells will result in a superior therapy for the treatment of hearing loss.

Public Health Relevance

The long-term goal of this research is to treat hearing loss with more effective therapies than provided by hearing aids or cochlear implants. Specifically, this research is designed to investigate the basic mechanisms by which the auditory sensory cells, or hair cells, can regenerate in mammals. The overall hypothesis is that replacement of lost hair cells will result in a superior therapy for the treatment of hearing loss.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Small Research Grants (R03)
Project #
1R03DC010065-01
Application #
7649172
Study Section
Special Emphasis Panel (ZDC1-SRB-R (37))
Program Officer
Freeman, Nancy
Project Start
2009-06-01
Project End
2012-05-31
Budget Start
2009-06-01
Budget End
2010-05-31
Support Year
1
Fiscal Year
2009
Total Cost
$163,525
Indirect Cost
Name
Emerson College
Department
Other Clinical Sciences
Type
Schools of Arts and Sciences
DUNS #
043411438
City
Boston
State
MA
Country
United States
Zip Code
02116
Parker, Mark A; Cheng, Yen-fu; Kinouchi, Hikaru et al. (2014) An independent construct for conditional expression of atonal homolog-1. Hum Gene Ther Methods 25:1-13
Parker, Mark A (2011) Biotechnology in the treatment of sensorineural hearing loss: foundations and future of hair cell regeneration. J Speech Lang Hear Res 54:1709-31
Parker, Mark A; Jiang, Kevin; Kempfle, Judith S et al. (2011) TAK1 expression in the cochlea: a specific marker for adult supporting cells. J Assoc Res Otolaryngol 12:471-83
Parker, Mark; Brugeaud, Aurore; Edge, Albert S B (2010) Primary culture and plasmid electroporation of the murine organ of Corti. J Vis Exp :