The sensory hair cells of the inner ear detect sound and head movements. In humans and other mammals, hair cells can be lost, leading to permanent auditory and/or balance deficits. While mammalian hair cells do not regenerate after damage, hair cells of non-mammalian vertebrates including fish and chickens can regenerate. Although the signaling mechanisms regulating the formation of new hair cells are not fully understood, the underlying supporting cells, which act as a source for the new cells, are needed to regenerate the hair cells. The ciliary marginal zone serves a similar function in the retina, producing precursor cells that can differentiate into all of the cells types found in the retina throughout the lifetime of the animal. The zebrafish, Danio rerio, is a relatively new animal model to study sensory hair cell regeneration. Several different mutant zebrafish lines that have smaller eyes and reduced cellular proliferation in the ciliary marginal zone have been identified. If the role of supporting cells in the ear is comparable to that of the ciliary marginal zone in the retina, then these mutant fish may have defects in sensory hair cell development or regeneration. Preliminary data indicate that these mutants have fewer hair cells. There are four aims to study the mechanisms regulating the production and regeneration of hair cells.
In specific aim 1, the structure of the hair cells in mutant zebrafish using light and in some cases, electron microscopy. We hypothesize that the reduced numbers of hair cells may be due to a reduction in cell proliferation, an increase in cell death or a combination of both.
In specific aim 2, the rates of both ongoing supporting cell proliferation and hair cell death will be determined. We will also examine the regenerative capabilities of the mutants following aminoglycoside administration since like supporting cells of the inner ear, the cells progenitor cells in the retina proliferate, differentiate and replace damaged cells so these mutants may have abnormal hair cell regenerative capabilities.
In specific aim 3, the mutated genes of two of our mutants will be identified using mapping techniques.
In specific aim 4, we will participate in an ongoing mutagenesis screen to identify other mutant lines. Research into the genetics regulating supporting cell proliferation in non-mammalian vertebrates has direct relevance to humans, since defects in sensory systems that normally proliferate may reveal genes that regulate the number of cells in the quiescent mammalian ear.
We propose to characterize the sensory hair cells of mutant zebrafish that have smaller eyes and identify the genes associated with these mutant fish. The mechanisms regulating eye growth has been hypothesized to be similar to those mechanisms regulating the regenerative ability of fish to hear following deafening. By better understanding these processes, this will allow us to develop strategies to restore hearing and/or balance problems in humans.
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