The long-term goals are to identify in the sensory epithelia of the zebrafish. The identification of genetic mechanisms involved in the generation and regeneration of hair cells is potentially of great practical importance because the components of these mechanisms may be used to trigger hair cell regeneration in the human auditory system. Understanding the genetics of hair cell maintenance might lead to new treatment regimens for progressive hearing loss. The small quantities of tissue available from the vertebrate inner ear constrain the understanding of the molecular biology of the inner ear to genes expressed in high quantity or to those affected in naturally occurring mutations in (primarily) man and mouse. Zebrafish forward genetic analysis, through random mutagenesis approaches, provides an opportunity to find genes that may be critical, but expressed in very small quantities. Although the mammalian inner ear is more complex than that of the fish, the fundamental elements of inner ear function appear to be the same in both. To identify such genes, we propose to screen for recessive deafness in chemically mutagenized fish using F2 parthenogenetic diploids.
The specific aims are: (1) to use chemical mutagenesis and early pressure to generate parthenogenetic diploid embryos from the progeny of mutangenized fish; (2) to search for defects in hair cell generation, regeneration, function, and maintenance by screening for morphological defects in inner ear structures in early larvae; for balance problems in larvae; for defects in hair cell generation in the lateral line organ with a hair cell selective fluorescent dye (daspei); for defects in hair cell regeneration after neomycin induced destruction of hair cells, and for functional defects in hearing at day 7 and at 3 months with an automated behavioral screen that uses image analysis of the startle response to acoustic stimulation.; (3) to genetically characterize the mutants that are isolated (4) to determine the developmental and cellular bases of the isolated mutant phenotypes.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC005103-03
Application #
6634560
Study Section
Special Emphasis Panel (ZRG1-BIOL-1 (02))
Program Officer
Freeman, Nancy
Project Start
2001-07-01
Project End
2005-05-31
Budget Start
2003-06-01
Budget End
2004-05-31
Support Year
3
Fiscal Year
2003
Total Cost
$222,000
Indirect Cost
Name
Massachusetts Eye and Ear Infirmary
Department
Type
DUNS #
073825945
City
Boston
State
MA
Country
United States
Zip Code
02114
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Tsujikawa, Motokazu; Malicki, Jarema (2004) Intraflagellar transport genes are essential for differentiation and survival of vertebrate sensory neurons. Neuron 42:703-16