The loss of sensory hair cells from the human ear is a leading cause of hearing and balance disorders. Although the potential for regeneration in the human ear is very limited, the ears of nonmammalian vertebrates can quickly regenerate after injury. A detailed understanding of the biological basis of this repair process should suggest methods for promoting similar forms of regeneration in humans. The overall goals of this study are to identify the biological signals that regulate hair cell phenotype and orientation during regeneration. One project will focus on the differentiation of vestibular hair cells. It has been known for over 50 years that the vestibular organs of higher vertebrates contain two distinct classes of sensory hair cell (which are known as type I and type II), yet we know nothing about the developmental origin of these two cell classes. Using newly-described markers for these cells, we will carry-out a quantitative characterization of the recovery of type I and type II hair cells during regeneration. A second project will examine how hair cell stereocilia reacquire their proper orientation during regeneration. We have found that regenerated hair cells in organ cultures of the avian ear are normally-oriented and our preliminary data suggest that molecules of the planar cell polarity (PCP) signaling pathway are critically involved in this process. A series of experiments will use in vitro methods to directly test the role of PCP signaling in regeneration. Finally, we will carry-out a detailed study of changes in the expression of core PCP molecules in the mammalian cochlea after ototoxic injury. Such knowledge will be crucial to all current efforts aimed at the induction of biological repair in the mammalian inner ear.

Public Health Relevance

The loss of sensory hair cells from the human ear is a leading cause of permanent hearing disorders. The proposed research projects focus on the mechanisms of biological repair in the ear, so as to restore sensory function. The emphasis will be on the reformation of normal patterns of hair cell phenotype and orientation during the regenerative process.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC006283-07
Application #
7915256
Study Section
Auditory System Study Section (AUD)
Program Officer
Freeman, Nancy
Project Start
2003-07-01
Project End
2012-03-31
Budget Start
2010-08-01
Budget End
2012-03-31
Support Year
7
Fiscal Year
2010
Total Cost
$380,000
Indirect Cost
Name
Washington University
Department
Otolaryngology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Ohlemiller, Kevin K; Kaur, Tejbeer; Warchol, Mark E et al. (2018) The endocochlear potential as an indicator of reticular lamina integrity after noise exposure in mice. Hear Res 361:138-151
Kaur, Tejbeer; Ohlemiller, Kevin K; Warchol, Mark E (2018) Genetic disruption of fractalkine signaling leads to enhanced loss of cochlear afferents following ototoxic or acoustic injury. J Comp Neurol 526:824-835
Hirose, Keiko; Rutherford, Mark A; Warchol, Mark E (2017) Two cell populations participate in clearance of damaged hair cells from the sensory epithelia of the inner ear. Hear Res 352:70-81
Warchol, Mark E; Stone, Jennifer; Barton, Matthew et al. (2017) ADAM10 and ?-secretase regulate sensory regeneration in the avian vestibular organs. Dev Biol 428:39-51
Kaur, Tejbeer; Zamani, Darius; Tong, Ling et al. (2015) Fractalkine Signaling Regulates Macrophage Recruitment into the Cochlea and Promotes the Survival of Spiral Ganglion Neurons after Selective Hair Cell Lesion. J Neurosci 35:15050-61
Kaur, Tejbeer; Hirose, Keiko; Rubel, Edwin W et al. (2015) Macrophage recruitment and epithelial repair following hair cell injury in the mouse utricle. Front Cell Neurosci 9:150
Tong, Ling; Strong, Melissa K; Kaur, Tejbeer et al. (2015) Selective deletion of cochlear hair cells causes rapid age-dependent changes in spiral ganglion and cochlear nucleus neurons. J Neurosci 35:7878-91
Ku, Yuan-Chieh; Renaud, Nicole A; Veile, Rose A et al. (2014) The transcriptome of utricle hair cell regeneration in the avian inner ear. J Neurosci 34:3523-35
Slattery, Eric L; Oshima, Kazuo; Heller, Stefan et al. (2014) Cisplatin exposure damages resident stem cells of the mammalian inner ear. Dev Dyn 243:1328-37
Huh, Sung-Ho; Jones, Jennifer; Warchol, Mark E et al. (2012) Differentiation of the lateral compartment of the cochlea requires a temporally restricted FGF20 signal. PLoS Biol 10:e1001231

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