Sensorineural hearing loss and vestibular disorders result primarily from the loss of sensory hair cells. The broad long-term goal of the proposed research is to develop methods for the treatment of sensorineural hearing loss and vestibular disorders based on understanding the molecular signals regulating hair-cell regeneration in avian and rodent models. Virtually nothing is known regarding the factors involved in the initiation and regulation of hair-cell genesis and differentiation in either the mature or developing inner ear. The experiments outlined in this proposal will test two specific hypotheses: (1) that growth factors are important in regulating the proliferation of hair-cell progenitors, and (2) that macrophages are important in initiating and regulating hair-cell regeneration, perhaps through their release of growth factors, cytokines, or proteases. The first hypothesis will be tested by (1) adding known growth factors to mature, cultured inner-ear epithelium and assessing the effects on cellular proliferation; (2) localizing growth factors and growth-factor receptors and their mRNA in normal and regenerating inner- ear epithelium; and (3) infusing growth factors into the in situ inner ear, and examining the effects on cellular proliferation. The hypothesis that macrophages are important in initiating and regulating the hair-cell regeneration response will be tested by determining whether media conditioned by activated monocytes can stimulate proliferation in cultured inner-ear sensory epithelia.

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 #
5R29DC002388-04
Application #
2443623
Study Section
Hearing Research Study Section (HAR)
Project Start
1994-07-01
Project End
1999-06-30
Budget Start
1997-07-01
Budget End
1998-06-30
Support Year
4
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of Washington
Department
Otolaryngology
Type
Schools of Medicine
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
Oesterle, E C; Bhave, S A; Coltrera, M D (2000) Basic fibroblast growth factor inhibits cell proliferation in cultured avian inner ear sensory epithelia. J Comp Neurol 424:307-26
Matsui, J I; Oesterle, E C; Stone, J S et al. (2000) Characterization of damage and regeneration in cultured avian utricles. J Assoc Res Otolaryngol 1:46-63
Oesterle, E C; Hume, C R (1999) Growth factor regulation of the cell cycle in developing and mature inner ear sensory epithelia. J Neurocytol 28:877-87
Kuntz, A L; Oesterle, E C (1998) Transforming growth factor-alpha with insulin induces proliferation in rat utricular extrasensory epithelia. Otolaryngol Head Neck Surg 118:816-24
Bhave, S A; Oesterle, E C; Coltrera, M D (1998) Macrophage and microglia-like cells in the avian inner ear. J Comp Neurol 398:241-56
Kuntz, A L; Oesterle, E C (1998) Transforming growth factor alpha with insulin stimulates cell proliferation in vivo in adult rat vestibular sensory epithelium. J Comp Neurol 399:413-23
Oesterle, E C; Lurie, D I; Rubel, E W (1997) Neurofilament proteins in avian auditory hair cells. J Comp Neurol 379:603-16
Oesterle, E C; Tsue, T T; Rubel, E W (1997) Induction of cell proliferation in avian inner ear sensory epithelia by insulin-like growth factor-I and insulin. J Comp Neurol 380:262-74
Yamashita, H; Oesterle, E C (1995) Induction of cell proliferation in mammalian inner-ear sensory epithelia by transforming growth factor alpha and epidermal growth factor. Proc Natl Acad Sci U S A 92:3152-5