It is estimated that 80% of significant hearing impairment in the U.S. results from sensorineural or so-called """"""""nerve"""""""" deafness, that usually is due to damage to or loss of the sensory hair cells that convert sound energy into electrical activity in the inner ear. This has been considered irreversible, because the production of hair cells in the human ear ceases before birth. However, these cells are produced throughout life in cold-blooded animals; in some, millions of new hair cells are added in the ear, in others hair cells can be regenerated. Also, during the last grant cycle, it was discovered that damaged hair cells in the cochleae of birds could be replaced through a process of regenerative proliferation, that could be evoked by trauma in auditory cell populations that are mitotically quiescent in undamaged ears. This application for renewal of a project in its eighth year, proposes a series of studies that will continue to investigate the cellular processes that underlie hair cell production and regenerative replacement of hair cells lost during postembryonic life. The discovery of trauma-induce regeneration in a warm-blooded animal's cochlea has provided additional support for the central thesis, that the obstacles to regeneration of hair cells in the ears of mammals are not likely to remain insurmountable, if the control of the postembryonic production of hair cells in other ears can be understood at cellular and molecular levels. The project will use the methods of tritiated-thymidine autoradiography, immunocytochemistry, electron microscopy, laser-microbeam ablation of individual cells, time-lapse video microscopy of in vivo preparations of regenerating hair cell epithelia in the lateral line system of salamanders and in vitro preparations of sensory epithelia from the frog sacculus, the chicken cochlea, and the developing organ of Corti of rodents. The objectives are: 1) definitive identification of the progenitor cells that give rise to replacement hair cells during regeneration, 2) evaluation of the potential role of hypothesized triggers that may initiate the process of regeneration, and 3) the determination of the conditions that are necessary for regeneration of hair cells to run to completion. The information sought is essential to understanding the capacities of regeneration and self-repair in hair cell epithelia. This directly pertains to possible recovery from sensorineural hearing loss and balance disorders, and to an understanding of the development of normal and abnormal function in human ears.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC000200-12
Application #
2125077
Study Section
Neurology B Subcommittee 2 (NEUB)
Project Start
1988-12-01
Project End
1995-11-30
Budget Start
1993-12-01
Budget End
1994-11-30
Support Year
12
Fiscal Year
1994
Total Cost
Indirect Cost
Name
University of Virginia
Department
Otolaryngology
Type
Schools of Medicine
DUNS #
001910777
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Thiede, Benjamin R; Corwin, Jeffrey T (2014) Permeation of fluorophore-conjugated phalloidin into live hair cells of the inner ear is modulated by P2Y receptors. J Assoc Res Otolaryngol 15:13-30
Mann, Zoƫ F; Thiede, Benjamin R; Chang, Weise et al. (2014) A gradient of Bmp7 specifies the tonotopic axis in the developing inner ear. Nat Commun 5:3839
Burns, Joseph C; Corwin, Jeffrey T (2014) Responses to cell loss become restricted as the supporting cells in mammalian vestibular organs grow thick junctional actin bands that develop high stability. J Neurosci 34:1998-2011
Burns, Joseph C; Corwin, Jeffrey T (2013) A historical to present-day account of efforts to answer the question: ""what puts the brakes on mammalian hair cell regeneration?"". Hear Res 297:52-67
Burns, Joseph C; Collado, Maria Sol; Oliver, Eric R et al. (2013) Specializations of intercellular junctions are associated with the presence and absence of hair cell regeneration in ears from six vertebrate classes. J Comp Neurol 521:1430-48
Bermingham-McDonogh, Olivia; Corwin, Jeffrey T; Hauswirth, William W et al. (2012) Regenerative medicine for the special senses: restoring the inputs. J Neurosci 32:14053-7
Burns, Joseph C; On, Doan; Baker, Wendy et al. (2012) Over half the hair cells in the mouse utricle first appear after birth, with significant numbers originating from early postnatal mitotic production in peripheral and striolar growth zones. J Assoc Res Otolaryngol 13:609-27
Collado, Maria Sol; Burns, Joseph C; Meyers, Jason R et al. (2011) Variations in shape-sensitive restriction points mirror differences in the regeneration capacities of avian and mammalian ears. PLoS One 6:e23861
Collado, Maria Sol; Thiede, Benjamin R; Baker, Wendy et al. (2011) The postnatal accumulation of junctional E-cadherin is inversely correlated with the capacity for supporting cells to convert directly into sensory hair cells in mammalian balance organs. J Neurosci 31:11855-66
Goodyear, Richard J; Legan, P Kevin; Christiansen, Jeffrey R et al. (2010) Identification of the hair cell soma-1 antigen, HCS-1, as otoferlin. J Assoc Res Otolaryngol 11:573-86

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