The death of sensory hair cells in the inner ear causes irreversible hearing loss and balance deficits in humans and other mammals. In non-mammalian vertebrates, hair cell death elicits a regenerative response in neighboring supporting cells which can include both proliferation and differentiation into replacement hair cells. These repair processes are observed in mammals at early developmental stages, yet decline during maturation (e.g. the first postnatal week in mice). The cause of this reduction in supporting cell regenerative responses remains undefined. A better understanding of the signals controlling supporting cell proliferation will aid efforts to identify the limitations of hair cell regeneration in mammals, and ultimately could lead to therapies that restore sensory function. Supporting cell shape changes are an early event in the regenerative response associated with proliferation (Cotanche 1987; Meyers et al. 2007), and mechanical signals are now recognized as a key mediator of cell behavior. This leads to the hypothesis that mechanical signals arising from cell loss stimulate regenerative proliferation in supporting cells. This project has three aims to test hypothesized ?triggers? and ?brakes? of sensory hair cell regeneration related to mechanical signaling. The first investigates mechanosensory pathways with well-established roles in tissue regeneration that remain relatively unexplored in the inner ear.
The second aim tests whether the signals that initiate proliferation are specific to the loss of hair cells, or rather are more general cues related to loss of other cell types in the sensory epithelium.
The final aim i s to identify proteins that impart unique thickness and stability to the apical F-actin belts of mature mammalian supporting cells, which are hypothesized to limit hair cell regeneration in mammals.

Public Health Relevance

This research will test the hypothesis that mechanical signals are a prominent mediator of regeneration of sensory hair cells in the inner ear. It will also reveal candidate genes which may limit regeneration in mature mammals by impeding such signals. This ultimately could lead to therapies which ameliorate the irreversible hearing and balance deficits afflicting millions of Americans.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
5F30DC016806-02
Application #
9589433
Study Section
Special Emphasis Panel (ZDC1)
Program Officer
Rivera-Rentas, Alberto L
Project Start
2017-08-22
Project End
2020-08-21
Budget Start
2018-08-22
Budget End
2019-08-21
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Virginia
Department
Neurosciences
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904