It is estimated that 10% of the population is affected by sensorineural or "nerve" deafness that usually arises from sensory hair cell loss or damage. Sensory deficits resulting from hair cell loss have been considered irreversible because the production of human hair cells ceases before birth. In contrast, hair cells are produced postembryonically in the ears of cold-blooded and some warm-blooded vertebrates (birds), and thousands of new hair cells can be replaced through trauma-evoked regenerative proliferation. Findings showing that supporting cells can proliferate in the balance organs of mature mammals and auditory organ of neonatal mammals under certain circumstances suggest that hair cell regeneration may be inducible in the human ear someday. In order to develop clinical therapies that will bring about hair cell regeneration in the human ear, we must identify the cellular and molecular signals responsible for triggering the regenerative proliferation of inner ear supporting cells after hair cell death, and determine how these cells go on to form hair cells. The goal of the proposed research is to identify factors that regulate regenerative replacement of hair cells in the ears of warm-blooded vertebrates during postembryonic life. This application proposes to investigate the following hypotheses: 1) Members of the TGF2 superfamily regulate progenitor cell proliferation in mature inner ear sensory receptor epithelia, and 2) Robust regenerative proliferation of progenitor cells in mature inner ear sensory epithelia may require a simultaneous release from tonic negative regulation coupled with mitogenic signaling by the TGF2 pathway. These hypotheses will be tested using a combination of techniques, including cell culture, quantitative RT-PCR, cell localization, and mouse genetics.
Inner ear sensory hair cell loss in humans is permanent and cumulative, whereas non-mammalian vertebrates robustly make new hair cells to replace those that have been lost after damage. We seek to identify ways to stimulate hair cell regeneration in humans by inducing cells in the mature sensory receptor epithelia to proliferate. We are investigating the role of transforming growth factor beta (TGF2) signaling in regulating the proliferation of progenitor cells in mature inner ear sensory epithelia.
|Oesterle, Elizabeth C; Chien, Wei-Ming; Campbell, Sean et al. (2011) p27(Kip1) is required to maintain proliferative quiescence in the adult cochlea and pituitary. Cell Cycle 10:1237-48|
|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|
|McCullar, Jennifer S; Ty, Sidya; Campbell, Sean et al. (2010) Activin potentiates proliferation in mature avian auditory sensory epithelium. J Neurosci 30:478-90|
|Lentz, Jennifer J; Gordon, William C; Farris, Hamilton E et al. (2010) Deafness and retinal degeneration in a novel USH1C knock-in mouse model. Dev Neurobiol 70:253-67|
|McCullar, Jennifer S; Oesterle, Elizabeth C (2009) Cellular targets of estrogen signaling in regeneration of inner ear sensory epithelia. Hear Res 252:61-70|
|Oesterle, Elizabeth C; Campbell, Sean (2009) Supporting cell characteristics in long-deafened aged mouse ears. J Assoc Res Otolaryngol 10:525-44|
|Oesterle, Elizabeth C; Campbell, Sean; Taylor, Ruth R et al. (2008) Sox2 and JAGGED1 expression in normal and drug-damaged adult mouse inner ear. J Assoc Res Otolaryngol 9:65-89|
|Bermingham-McDonogh, Olivia; Oesterle, Elizabeth C; Stone, Jennifer S et al. (2006) Expression of Prox1 during mouse cochlear development. J Comp Neurol 496:172-86|
|O'Halloran, Elizabeth K; Oesterle, Eliazabeth C (2004) Characterization of leukocyte subtypes in chicken inner ear sensory epithelia. J Comp Neurol 475:340-60|
|Hume, Clifford R; Kirkegaard, Mette; Oesterle, Elizabeth C (2003) ErbB expression: the mouse inner ear and maturation of the mitogenic response to heregulin. J Assoc Res Otolaryngol 4:422-43|
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