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many as 1 in 1000 children are born in the United States with
a handicapping hearing loss. And it is rapidly becoming evident
that at least 50% of these children will have a hearing loss
that is hereditary/genetic in nature. Accordingly, it is imperative
that we understand the genetic processes guiding development
of the ear and normal hearing.
The Laboratory of Developmental Otology is focusing its efforts
on identifying and characterizing the expression of genes
critical during development of the inner ear. By studying
these genes in animal models, it is possible to identify,
characterize and experimentally manipulate genes important
for normal ear development. In addition, analysis of mutant
mice has allowed us to determine the effects on ear development
when there is a loss of specific gene function.
The otocyst gives rise to the cochlea (the auditory/hearing
organ of the inner ear), the semicircular canals (balance
organs) as well as the endolymphatic duct and sac (structures
believed to play a role in maintaining the normal fluid environment
in the inner ear). Failure to develop any of these structures
in humans results in deafness, balance disturbances or both.
Our investigations are aimed at defining which genes control
this intricate developmental process and what the consequences
are when these genetic mechanisms fail.
As an example, we are studying kreisler mice - a mutant strain
first identified in the 1940's. Kriesler mice are deaf and
circle (typical behaviors for mice with inner ear defects).
Analysis has shown that kreisler mice fail to develop an endolymphatic
duct and sac and subsequently development very rudimentary
inner ears. Genetic studies have since demonstrated that these
defects are due to mutation of the kreisler gene. This gene
is a transcription factor - a gene which regulates the activity
of other genes - that is expressed (turned on) during the
earliest stages of ear development. Studies are being conducted
to determine which subsequent genes are affected by kreisler
mutation and whether experimental restoration of kreisler
activity can rescue normal inner ear development.
Another line of investigation investigates the role of Aquaporins
(a family of waterchannel proteins) in the developing inner
ear. The reason for examining these genes is based upon the
unique fluid environment in the inner ear that is essential
for the ear to perform its functions of hearing and maintaining
balance. The fluid contained within the inner ear (endolymph)
is unique in having an extremely high potassium and low sodium
concentration compared to the surrounding fluids. In addition,
the fluid compartment within the inner ear maintains an electrical
gradient of +80 millivolts compared to the surrounding environment.
This unusual electro-chemical milieu allows the ear to generate
nerve impulses in response to incoming sound or changes in
position. Failure to develop or maintain this fluid environment
precisely can result in deafness, balance disorders and/or
tinnitus. Diseases such as Meniere's Disease, for example,
are felt to be due (in some cases) to a failure of regulation
of the normal inner ear fluid environment.
To date, very little data are available that explain how
the inner ear maintains this precise fluid balance. The study
of aquaporins provides a line of investigation that may help
elucidate how this key inner ear process develops and is maintained.
By studying when and where these waterchannels are expressed
in the inner ear, it may be possible to determine how the
inner ear transports water into and out of the endolymph and
thereby regulates this fluid balance.
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