Protecting Hearing from Ototoxic Drugs – Lisa Cunningham, NIH


>>Research in our laboratory
is focused on hearing loss and specifically we study the
sensory cell in the inner ear that transduces sound energy
into neural input to the brain. This is a model of the inner ear and there are actually six
organs in the inner ear. The snail-shaped
cochlea is here, and this is the hearing organ. And there are five organs here
in what’s the vestibular system that are responsible
for balance function. Each of these six sensory organs
in the inner ear utilizes, as the sensory receptor cell, a cell type that’s called a hair
cell, which is diagrammed here. It’s called a hair cell
because on the apical surface of the cell is a bundle of
stiff actin-based stereocilia. And when the fluid spaces
in the inner ear move, it causes this stereocilia
bundle to be deflected. And that deflection opens a
mechanically-gated ion channel that depolarizes this
cell and causes the cell to release neurotransmitter. And that neurotransmitter
is then sent as neural input to the brain. And each of these sensory hair
cells is completely surrounded in the inner ear by
another cell type, which is schematized
here in green. And these are called
supporting cells, and supporting cells
are glia-like cells that serve functions that are
reminiscent of both astrocytes and microglia in the
central nervous system. And sensory hair cells
are susceptible to death from a variety of stresses. These include aging,
certain genetic mutations, exposure to too much noise can
definitely kill these cells, and in our lab we study hair
cell death that is caused by exposure to therapeutic drugs
that are given in the clinic to treat life-threatening
disorders. And these drugs have, as a
side effect, that they’re toxic to these sensory hair
cells in the inner ear. There are two major
classes of these drugs that cause hearing loss. One class is the
aminoglycoside antibiotics. They’re among the
most widely-used and successful antibiotics
in the world, but they cause a significant
permanent hearing loss in about 25 percent of
patients who receive the drugs. The other major class of drugs that kills these cells is the
anti-cancer drug, cisplatin, which is easily the
most widely used and effective anti-cancer
drug in the world. This is a terrific drug,
it saves millions of lives, but it also causes significant
permanent hearing loss in a, in a high proportion of the
people who take the drug.>>We imaged these hair cells
dying, so we give them drugs that cause those hair cells
to die, and then we look at what the supporting cells
do once those hair cells die, some different types of drugs. And so what we can see is
that when a hair cell is sort of on the cusp of dying,
just before it dies, or just after it dies,
we’re still trying to figure out exactly which. The supporting cell comes in and
squeezes that hair cell right, right at the top, just,
just under the very top, and it sort of breaks that neck,
decapitating that hair cell. Then it comes in and cleans up
the rest of that dead hair cell, sort of keeping the, the
tissue relatively clean. And so we image that process and
we see how it differs depending on which drug we’re
giving the tissue.>>There are two major questions
under study in our laboratory. First is why do these drugs
cause sensory hair cell death, and what are the cellular
and molecular mechanisms that determine whether
a sensory hair cell, when it’s under stress,
will ultimately live or die?>>Our recent experiments have
shown that supporting cells, in response to hair cell
stress, will secrete molecules that protect and prevent
hair cells from dying. This is exciting because
this means that these signals of survival and death are
coming from the supporting cells and not the hair cell itself. This is also exciting
because this means that the supporting
cells are actually able to sense the stress that the
hair cell is going under, and be able to prevent these
stress hair cells from dying. My current experiments
are focusing on determining how the
supporting cells are receiving and responding to
the hair cell stress, and the molecular mechanisms by which they protect
the hair cells.>>The second question
under study in the laboratory
is translational, and that is how do we
use this information about hair cell death
and hair survival to develop clinical therapies
that will protect the inner ear in patients receiving
these drugs. We know that in a
variety of systems, you can stress the
system a little bit and induce a stress-induced
protective response. So that’s what this
project is about. And what we’ve been doing is
treating animals with noise, a level of noise that is loud
enough to stress the inner ear, but not loud enough to cause
a noise-induced hearing loss. So we’re sort of
threading the needle there. And when we do that, we can generate an
intrinsic protective response in the inner ear that can
protect the hair cells, according to Shoman’s
[phonetic] data, against this ototoxic
drug-induced hearing loss. So, some of that work is
going on in this room. What Andrew is doing is
dissecting a cochlea from one of these animals, and so this
is what the adult mouse cochlea looks like, and we
call this the apex, and the cochlea is a
snail-shaped organ that spirals around to the base down here. We hear low frequencies
here at the apex and high frequencies
here at the base. And there are hair cells
all along this epithelium. And so Andrew will dissect this
cochlea apart, and prepare it in a way that will allow
us to evaluate the health of the hair cells and
the supporting cells. And Shoman is looking
at a cochlea that has already been
prepared in this manner and this microscope
allows us to do that. And what Shoman’s preparation
shows is the three rows of outer hair cells, if
you would point those out, there are three rows
of outer hair cells which are these red pieces, red
cells here, and a single row of inner hair cells, and this is
what the adult mammalian cochlea looks like when it’s
nice and healthy. And one of the lovely
things about being at NIH is that the NIH Clinical Center
has the largest center for clinical trials
in the world, and so there are patients there who are already receiving
these drugs, the ototoxic aminoglycoside
antibiotics and cisplatin, so we can partner with our
partners at the clinical center to see if we can
develop a therapy that can protect the
hearing in those patients.

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