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Researchers learn more about ways to
regenerate the ear's hearing cells
Followup study finds gene knockout
has different effects in specific areas of inner ear
BOSTON - April 28, 2006 - Massachusetts General Hospital
(MGH) researchers have made important progress in their ongoing
effort to regenerate the inner ear's hair cells, which convert sound
vibrations to nerve impulses. In an upcoming issue of Proceeding
of the National Academy of Sciences they report successfully
creating a mouse model that allows them to build on earlier findings
about the effect of deactivating a protein that controls the growth
and division of hair cells. The paper, which is receiving early
online publication, also finds that suppressing the retinoblastoma
(Rb) protein has different effects in specific parts of the inner
ear.
"In these first studies of the role of the Rb protein in the
ears of postnatal mice, we have confirmed that - under the right
conditions - mature hair cells can go through the cell cycle and
produce new, functioning hair cells. But we've also confirmed that
you need to block Rb reversibly and at an early stage of development,
otherwise the hair cells will die," says Zheng-Yi Chen, DPhil,
of the MGH Neurology Service, the study's senior author. In 2005
Chen was named to the Scientific American 50, the magazine's annual
list of outstanding leaders, for this continuing research project.
Named for the hair-like projections on their surfaces, hair cells
form a ribbon of vibration sensors along the length of the cochlea
- the organ of the inner ear that senses sound - where they convert
sonic vibrations to electrical signals that are carried to the brain.
The cells are very sensitive to damage from excessive noise, infections
and toxins. Once damaged, hair cells do not naturally regenerate
in mammals, and their death accounts for most types of acquired
hearing loss.
All cells grow and divide through a process called the cell cycle,
and many proteins have been identified that control different cell
cycle phases. In 2005 Chen's group published a paper in the journal
Science
reporting that the Rb protein, known to suppress the cell cycle,
could be important for halting the cell cycle in hair cells. They
used a genetically modified mouse strain in which Rb was no longer
made in the inner ear. By examining the inner ears of mouse embryos
- that strain did not survive past birth - the researchers found
more hair cells in the knockout mice than in the ears of normal
mice at the same stage of development. The additional cells looked
and functioned like normal hair cells and appeared to be actively
regenerating.
For this followup study, the researchers developed a new strain
of inner-ear Rb-knockout mice that survive for up to six months
past birth. Their investigation of the effects of Rb deletion on
the hair cells of the inner ear finds differences between the auditory
portion of the organ, which controls hearing, and the vestibular
area, which is involved with balance. While the Rb-negative auditory
hair cells in early postnatal mice are dividing and growing, the
cells do not mature properly and eventually die, resulting in the
mice becoming deaf by the age of 3 months. Vestibular hair cells,
however, appear to grow and mature relatively normally and continue
cell division even in mature mice. Adult Rb-knockout mice maintain
some vestibular function, indicating that those hair cells are contributing
to their sense of balance at the system level.
"We've shown that vestibular hair cell regeneration may be
achieved and may be less of an obstacle than auditory cell regeneration,"
Chen says. "Now we need to find ways to create a similar system
in the auditory cells, and this new model will help us better understand
the mechanisms behind functional hair cell regeneration. Our next
step will be developing a transient, reversible block of Rb function
to assess its role in both types of hair cell." Chen is an
assistant professor of Neurology of Harvard Medical School (HMS).
The report's co-authors are first author Cyrille Sage, PhD, and
Mingqian Huang, PhD, of the MGH; Melissa Vollrath, PhD, and David
Corey, PhD, Howard Hughes Medical Institute and HMS; M. Christian
Brown, PhD, Mass. Eye and Ear Infirmary; Douglas E. Vetter, PhD,
and Philip Hinds, PhD, Tufts-New England Medical Center. The research
was supported by grants from the National Institutes of Health,
the Howard Hughes Medical Institute and a Pfizer/AFAR Innovations
in Aging Research Grant.
Massachusetts General Hospital, established in 1811, is the original
and largest teaching hospital of Harvard Medical School. The MGH
conducts the largest hospital-based research program in the United
States, with an annual research budget of nearly $500 million and
major research centers in AIDS, cardiovascular research, cancer,
computational and integrative biology, cutaneous biology, human
genetics, medical imaging, neurodegenerative disorders, regenerative
medicine, transplantation biology and photomedicine. MGH and Brigham
and Women's Hospital are founding members of Partners HealthCare
HealthCare System, a Boston-based integrated health care delivery
system.
Media Contact: Sue
McGreevey, MGH Public Affairs
Physician Referral Service: 1-800-388-4644
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