Millions of Americans are affected by permanent hearing deficits and balance dysfunctions that result from losses of sensory hair cells. In mammalian ears, when hair cells die they are not effectively replaced, but the case is quite different in non- mammalian vertebrates. In those species hair cell loss leads to cell proliferation and the subsequent differentiation of new replacement hair cells, which then become innervated. These regenerative events lead to structural healing of damaged ears and can restore hearing and balance a few weeks after non-mammalian vertebrates have experienced damage that would result in permanent deficits for humans. Research has shown that human and rodent ear tissues can activate important elements of the biological machinery that underlies regeneration, but the regenerative responses in mammalian ears are normally limited. The research proposed seeks knowledge that may provide the means to eventually overcome those limits. This request for renewal of a project in its 24th year proposes to continue investigations that focus on identifying and understanding the signaling mechanisms that control the production of cells and the processes that lead to their specialization as sensory hair cells in embryonic and postembryonic ears. The mechanisms that limit self-repair in the ears of mammals will be investigated and treatments that may overcome those limits will be tested. The information sought may identify targets for the development of therapeutic approaches to stimulate self-repair in the ears of mammals. In addition, this project will seek to scale up the in vitro production of hair cells from lines of passaged cells. The availability of specialized cells that are produced in vitro has provided the basis for many examples of significant gains in cancer cell biology, neurology, and other fields. These cell lines and the knowledge gained in their further development and utilization holds the potential for contributing to improved treatments for diseases of the ear. The goals of this research directly pertain to possible recovery from sensorineural hearing loss and balance dysfunctions that contribute to prevalent communication disorders and to falls by elderly individuals. They also are likely to lead to improved understanding of the development of normal and abnormal auditory and vestibular function in human ears. With the proposed investigations, we seek to contribute to better understanding of the cellular lineages and the cellular mechanisms that contribute to the development, regenerative replacement, and in vitro production of inner ear hair cells. Hair cell loss is the leading cause of permanent hearing impairment as well as a contributing cause of balance impairments that can lead to falls in older individuals. The knowledge we seek holds the potential to ultimately contribute to the development of treatments that may lead to partial or complete recovery from forms of hearing or balance impairment that are now permanent.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC000200-28
Application #
8288600
Study Section
Auditory System Study Section (AUD)
Program Officer
Freeman, Nancy
Project Start
1988-12-01
Project End
2013-11-30
Budget Start
2012-07-01
Budget End
2013-11-30
Support Year
28
Fiscal Year
2012
Total Cost
$482,747
Indirect Cost
$164,688
Name
University of Virginia
Department
Neurosciences
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Mann, Zoë 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
Thiede, Benjamin R; Mann, Zoë F; Chang, Weise et al. (2014) Retinoic acid signalling regulates the development of tonotopically patterned hair cells in the chicken cochlea. Nat Commun 5:3840
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
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
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
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
Collado, Maria Sol; Burns, Joseph C; Hu, Zhengqing et al. (2008) Recent advances in hair cell regeneration research. Curr Opin Otolaryngol Head Neck Surg 16:465-71
Burns, Joseph; Christophel, J Jared; Collado, Maria Sol et al. (2008) Reinforcement of cell junctions correlates with the absence of hair cell regeneration in mammals and its occurrence in birds. J Comp Neurol 511:396-414

Showing the most recent 10 out of 19 publications