$4.7 million grant sparks
stroke research collaboration
BY KRISTA CONGER
Many people might dismiss
dizziness, weakness, blurred vision and loss of muscle
coordination as simply the result of increasing age or
fatigue. But these symptoms, as well as a sudden, severe
headache, one-sided numbness and difficulty speaking or
understanding simple statements may signal a new or
recurring stroke -- a medical emergency that strikes more
than three-quarters of a million Americans each year.
Prompt treatment is vital
to preventing drastic consequences; strokes are the
leading cause of disability and the third most common
cause of death in the United States.
Now Stanford researchers
from several departments have joined forces to devise new
treatments to prevent the cellular mayhem that causes
stroke symptoms. The Center for Cerebrovascular Disease,
established with a $4.7 million grant from the National
Institute of Neurologic Disease and Stroke, will
consolidate the efforts of scientists from the
departments of neurosurgery, neurology and neurological
sciences, biological sciences and anesthesia in the
ambitious five-year effort. The researchers hope to
identify protective agents that can minimize the damage
done to neurons in the brain during a stroke.
"Having us all work
together and exchange ideas is a distinct
advantage," said Gary Steinberg, MD, PhD. Steinberg
is a professor and chair of the Department of
Neurosurgery and scientific director of the new program
project grant. "It's really a nice example of a
collaborative effort utilizing the talent we have at
Stanford in different departments."
That talent will be
focused on preventing the neuronal cell death that is the
hallmark of stroke. The damage is done when blood vessels
in the brain are blocked or suddenly rupture, depriving
areas of the brain of oxygen. As oxygen-starved cells
begin to die, they release toxic chemicals -- free
radicals -- that damage or kill surrounding cells and
tissues in a domino effect. The cellular carnage can
continue for several hours or days after the initial
event, leaving the patient with irreversible neurological
damage.
Participants in the Center
for Cerebrovascular Disease want to throw a wrench into
this cycle of destruction by identifying genes that might
protect neurons in this punishing environment. If
researchers can find a way to prompt these genes to turn
themselves on after a stroke, or administer a modified
virus to express these genes within the brain, some of
the neurons might be kept alive and functioning, they
theorize. But because the genes protect against -- but
don't repair -- cellular damage, any such treatment is a
race against the clock.
"We may have a three-
to four-day window for some types of stroke," said
Steinberg. "For other types we may have only three
to six hours to begin treatment."
During this time, neurons
in the stroke-affected region can die in two ways. A lack
of oxygen can cause the energy-generating machinery in
the affected cells to grind to a halt, releasing toxic
chemicals that can kill other cells and lead to a
localized region of tissue death, a process called
necrosis. Alternatively, a cell damaged by rampaging free
radicals released by its dying neighbors can initiate a
suicide program known as apoptosis.
In order to develop stroke
treatments that can interfere with either type of cell
death, the researchers are tackling the problem with a
three-pronged approach, studying individual cells in
culture as well as normal and genetically modified
rodents. In each model system, scientists are
investigating the effect of three classes of genes known
to play a role in deciding how and when cells die.
Hsp70 is a protein
produced in cells in response to stressful conditions,
such as higher than normal temperatures or lack of
oxygen. Excess production of hsp proteins in normal rats
has previously been shown by Steinberg's group to protect
neurons before a stroke is induced.
Steinberg's lab, together
with the laboratories of Robert Sapolsky, PhD, professor
of biological sciences and Midori Yenari, MD, assistant
professor of neurosurgery and of neurology and
neurological sciences, is studying the proto-oncogene
bcl-2. Bcl-2 has been implicated in both the apoptotic
and necrotic pathways of cell death. Recently the
scientists have identified a neuroprotective effect of
bcl-2 when administered even after a stroke has been
induced.
"With the most common
type of stroke we are able to protect by injecting
[bcl-2] an hour and half after the insult," said
Steinberg of the rodent experiments. This is potentially
good news for human stroke sufferers, whose condition
strikes without warning.
In addition to hsp70 and
bcl-2, Stanford researchers will study another class of
genes for potential neuroprotective effects. The
anti-oxidant enzymes SOD1, SOD2 and GSPx scavenge the
free radicals that can damage surrounding cells, possibly
preventing the cascade of death leading to neurological
impairment.
While Steinberg's
laboratory will collaborate with Yenari's group to
further investigate the effect of inducing the expression
of these genes in normal rats, the laboratory of Pak
Chan, PhD, professor of neurosurgery, will generate
genetically modified animals that over-express the genes
in question.
The laboratory of Rona
Giffard, MD, PhD, associate professor of anesthesia,
rounds out the center's team of cerebrovascular disease
experts. Together with the Sapolsky group, Giffard's
laboratory will test the effect of the genes at the level
of an individual cell in culture. This approach
eliminates many of the complexities encountered when
studying whole animals, and allows greater understanding
of what occurs at the molecular level during times of
oxygen deprivation.
"It's really
unique," said Steinberg of the collaborative
approach stimulated by the grant. "This is a program
project that incorporates people from five different labs
and four different departments." But departmental
differences aside, all of the researchers hope that their
molecular focus will increase understanding of the
pathophysiology of stroke and help pinpoint which of
these genes holds the most promise as a therapy for
stroke sufferers. SR
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