Mechanosensory transduction via intact hair cells is necessary for auditory and vestibular perception and thus is central to survival and communication in many species. Mammals do not demonstrate the capacity to regenerate hair cells post-embryologically. Thus, loss of hair cells leads to profound sensory deficits. In contrast, avian species produce vestibular hair cells continually throughout their life time, and they regenerate auditory and vestibular hair cells in response to damage. Avian hair cell regeneration occurs primarily by up-regulation of cell proliferation and differentiation of postmitotic cells into hair cells. These processes occur spontaneously in cultured avian inner ear epithelia. In cultured mammalian vestibular organs, some mitosis is stimulated by exogenous growth factors, suggesting that mammalian hair cell progenitors also have the capacity to divide. However, there is little experimental evidence that, in mammals, postmitotic cells are able to differentiate into hair cells. The broad goals of my research are to understand the cellular and molecular events that regulate hair cell production in the post-hatch chick and to apply this knowledge to eventually stimulate hair cell regeneration in mammals. The proposed experiments will use in vivo and in vitro approaches to identify molecules that regulate hair cell regeneration in the posthatch chick. Although several groups currently focus on events regulating mitosis of mature support cells in avian auditory and vestibular epithelia, relatively few studies are aimed at understanding how postmitotic cells are instructed to become hair cells. I will examine the role of intercellular signaling via the transforming growth factor beta (TGF()superfamily and via delta and serrate in the regulation of hair cell differentiation in the mature avian inner ear. Initial experiments will examine changes in receptor and ligand genes associated with these pathways in control and damaged avian hair cell epithelia. TGF(-related molecules that show changes in expression during regeneration will be added to cultured avian hair cell progenitors and infused into the intact avian inner ear to determine if they stimulate hair cell differentiation. If changes in delta and serrate expression accompany regeneration, I will examine the role of notch signaling in hair cell differentiation by perturbing notch expression in cultured avian hair cell progenitors. An understanding of how hair cell differentiation is regulated in mature vertebrates may lead to insight into the causes of congenital deafness and to therapeutic methods for curing hearing deficits.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29DC003696-05
Application #
6516182
Study Section
Hearing Research Study Section (HAR)
Program Officer
Freeman, Nancy
Project Start
1998-04-01
Project End
2003-08-31
Budget Start
2002-04-01
Budget End
2003-08-31
Support Year
5
Fiscal Year
2002
Total Cost
$107,426
Indirect Cost
Name
University of Washington
Department
Otolaryngology
Type
Schools of Medicine
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
Lewis, Rebecca M; Keller, Jesse J; Wan, Liangcai et al. (2018) Bone morphogenetic protein 4 antagonizes hair cell regeneration in the avian auditory epithelium. Hear Res 364:1-11
Chonko, Kurt T; Jahan, Israt; Stone, Jennifer et al. (2013) Atoh1 directs hair cell differentiation and survival in the late embryonic mouse inner ear. Dev Biol 381:401-10
Golub, Justin S; Tong, Ling; Ngyuen, Tot B et al. (2012) Hair cell replacement in adult mouse utricles after targeted ablation of hair cells with diphtheria toxin. J Neurosci 32:15093-105
Lin, Vincent; Golub, Justin S; Nguyen, Tot Bui et al. (2011) Inhibition of Notch activity promotes nonmitotic regeneration of hair cells in the adult mouse utricles. J Neurosci 31:15329-39
Brignull, Heather R; Raible, David W; Stone, Jennifer S (2009) Feathers and fins: non-mammalian models for hair cell regeneration. Brain Res 1277:12-23
Daudet, Nicolas; Gibson, Robin; Shang, Jialin et al. (2009) Notch regulation of progenitor cell behavior in quiescent and regenerating auditory epithelium of mature birds. Dev Biol 326:86-100