This proposal offers an exciting interdisciplinary approach to fundamental problems of cochlear function and dysfunction. It is based on current theories of regulatory mechanisms governing cell physiology and on novel molecular genetic approaches to the identification of genes and gene products. The unifying theme of cochlear homeostatic mechanisms is addressed in five projects representing molecular biology and genetics (Projects I, II and III) and molecular cell biology and biochemistry (Projects IV and V). The proposal combines diversified and powerful steps to investigate the normal system (Project V), the system under stress (Projects III and IV) and the genetically altered system (Projects I and II). Projects IV and V propose hypothesis-driven investigations related to the role of calcium in cochlear mechanisms (Project V) and to the function of heat shock proteins in cochlear trauma (Project IV). These studies are paired with the exciting new methods that molecular biology and genetics provide. Projects I and II propose positional cloning of mouse deafness mutants ames waltzer and pirouette, respectively. Project III uses auditory-specific trauma to identify genes by differential display. The interdisciplinary approach strengthened additionally by the resource available through the Kresge Hearing Research Institute. The Histology Core is responsible for providing morphological and histochemical assessments. Likewise, the Physiology Core will provide electrophysiological characterization of mutations, trauma and normal function. These cores are essential components of the Program Project, providing anatomical and functional feedback critical to the hypotheses and specific aims of other projects. In summary, the present proposal represents a broadly based yet focused approach to the study of molecular mechanisms in cochlear homeostasis. It is particularly powerful through its interdisciplinary nature and the ability to place molecular genetics and molecular biology into a systems context. As disease or dysfunction are an aberration of homeostatic mechanisms, the current studies will yield major fundamental information and enable us to design novel ways to prevent trauma to the inner ear or to accelerate recovery from such trauma.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Program Projects (P01)
Project #
3P01DC002982-04S2
Application #
6345528
Study Section
Communication Disorders Review Committee (CDRC)
Program Officer
Freeman, Nancy
Project Start
1997-01-01
Project End
2001-12-31
Budget Start
2000-09-01
Budget End
2000-12-31
Support Year
4
Fiscal Year
2000
Total Cost
$48,605
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Otolaryngology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Chen, Kejian; Godfrey, Donald A; Ilyas, Omer et al. (2009) Cerebellum-related characteristics of Scn8a-mutant mice. Cerebellum 8:192-201
Mustapha, Mirna; Beyer, Lisa A; Izumikawa, Masahiko et al. (2007) Whirler mutant hair cells have less severe pathology than shaker 2 or double mutants. J Assoc Res Otolaryngol 8:329-37
Cho, Younsook; Gong, Tzy-Wen L; Kanicki, Ariane et al. (2004) Noise overstimulation induces immediate early genes in the rat cochlea. Brain Res Mol Brain Res 130:134-48
Gong, Tzy-Wen L; Huang, Li; Warner, Steven J et al. (2003) Characterization of the human UBE3B gene: structure, expression, evolution, and alternative splicing. Genomics 82:143-52
Karolyi, I Jill; Probst, Frank J; Beyer, Lisa et al. (2003) Myo15 function is distinct from Myo6, Myo7a and pirouette genes in development of cochlear stereocilia. Hum Mol Genet 12:2797-805
Cho, Younsook; Gong, Tzy-Wen L; Stover, Timo et al. (2002) Gene expression profiles of the rat cochlea, cochlear nucleus, and inferior colliculus. J Assoc Res Otolaryngol 3:54-67
Mitchem, Kristina L; Hibbard, Ellen; Beyer, Lisa A et al. (2002) Mutation of the novel gene Tmie results in sensory cell defects in the inner ear of spinner, a mouse model of human hearing loss DFNB6. Hum Mol Genet 11:1887-98
Raphael, Y; Kobayashi, K N; Dootz, G A et al. (2001) Severe vestibular and auditory impairment in three alleles of Ames waltzer (av) mice. Hear Res 151:237-249
Stover, T; Nam, Y; Gong, T L et al. (2001) Glial cell line-derived neurotrophic factor (GDNF) and its receptor complex are expressed in the auditory nerve of the mature rat cochlea. Hear Res 155:143-51
Bespalova, I N; Van Camp, G; Bom, S J et al. (2001) Mutations in the Wolfram syndrome 1 gene (WFS1) are a common cause of low frequency sensorineural hearing loss. Hum Mol Genet 10:2501-8

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