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Cerebrovascular Research Program |
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The broad goal of
the Neurovascular Research Laboratory, established less than a year ago, is to
elucidate neurobiologic mechanisms that play a role in the pathogenesis of
cerebral ischemia and to explore the role and interaction of other cell types
with the neuron in various cerebrovascular disorders. Some of our specific
goals are outlined below.
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1. We seek to the understand the pathogenesis of cerebral vasospasm
resulting after subarachnoid hemorrhage (SAH) with the goal of identifying novel
therapeutics. Astrocytes, a type of glial cell and the most abundant cell
type in the brain, are anatomically located in juxtaposition to blood vessels
and participate in the development and maintenance of the blood-brain-barrier.
Traditionally, astrocytes have been regarded as a supportive cell, nourishing
neurons and maintaining homeostasis in the brain. However, recent work has
suggested that astrocytes may actively participate in brain function, including
protection of neurons during brain injury and in the control of cerebral blood
flow. In contrast to the recognized protective functions of glia, glial
pathologies may represent an important component of neurological disease that
has yet to be exploited. |
ventral view of
brain taken 1h post-
SAH in the murine model of SAH. |
Following SAH, inflammatory markers are rapidly increased
within the CSF, suggesting brain inflammation may contribute to the pathogenesis
of the complications of SAH, including the development of cerebral vasospasm and
secondary brain ischemia. However, the cell type(s) responsible for these
changes remains unknown. Presently, |
we are investigating the possible role of astrocytes in
this process, which may permit a better understanding of the mechanisms involved
in the development of cerebral vasospasm. Using a murine endovascular
perforation model of SAH, inflammatory genes were increased within hours of
brain injury. Interestingly, administration of an anti-inflammatory compound,
curcumin, prevented the development of secondary brain ischemia, suggesting
brain inflammation may contribute to the development of vasospasm. We also
observed a pronounced and rapid inflammatory response in cultured astrocytes,
leading to the hypothesis that astrocyte-derived inflammatory factors may
participate in the pathogenesis of subarachnoid hemorrhage and cerebral
vasospasm. Current work is focused on elucidating the
molecular mechanisms underlying the induction of inflammatory genes as a way to
develop targeted novel therapeutics to limit the development of cerebral
vasospasm and secondary brain ischemia following SAH.
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Placebo
150 mg/kg 300mg/kg
Curcumin protects against tMCAo
injury in the mouse - assessed by
TTC staining 24h post occlusion
(2h/22h perfusion) |
Ischemic stroke is a leading cause of death and
disability. Stroke-induced CNS injury is caused by a combination of
factors including oxidative stress, which is implicated in many
neurodegenerative diseases. We explored the ability of curcumin to protect
murine cortical neurons from |
H2O2-, NMDA-, and
hypoxia/reoxygenation-induced neuronal injury using a rodent suture model of
acute stroke. Our studies show that curcumin completely blocked the damage
induced by hypoxia/reoxygenation and by H2O2, and significantly reduced MNDA-induced
neuronal injury. The findings suggest that curcumin may be a powerful
compound to reduce oxidateive stress following ischemic brain injury.
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3. After menopause,
ovarian production of the steroid hormone 17b-estradiol
ceases. At this time women can ex-perience impaired cognitive functioning
and exhibit an increased risk of neuro-degenerative diseases. Our
laboratory is elucidating the molecular and cellular events underlyingthe
gender-specific protection of the brain and regulation of cognitive function.
Recently, we ident-ified estradiol-induced release of trans-forming growth
factor-b
from astrocytes |
Hierarchal clustering of
microarray data
taken from the cerebral cortex of rat
following treatment with
estrogen or tamoxifen. |
as an important component of neuroprotection against
stroke-induced injury. In collaboration with Dr. Darrell Brann (IMMAG;
Dept of Neurology), we have employed genomic and proteomic approaches to provide
a mechanistic understanding underlying estradiol-induced synapse formation.
This knowledge will provide molecular and cellular insights into the
gender-specific protection of the brain and regulation of cognition, which may
have implications for neuroprotection and brain repair following stroke.
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4. Another interest of the
laboratory is the role of astrocytes in the regulation of synaptic
plasticity. We have recently determined an astrocyte-derived
soluble factor(s) induces a robust increase in the expression of pre-
and post-synaptic markers in cultured cortical neurons. This
increase appears in both glutamergic and GABAergic neurons, suggesting
that astrocytes may globally enhance neuronal connectivity.
Current work is focused on the cellular regula-tion of these gene
changes, with an |
Effect of astrocyte-conditioned
media
on synapse formation (assessed by
spine marker, spinophilin) and post-
synaptic marker (PSD-95; seen as puncta)
in cultured cortical neurons. |
emphasis on the ERK/MAP kinase pathway.
These findings have relevance in the understanding of developmental
neuroscience. Furthermore, these pathways could potentially be
exploited to promote plasticity and “rewiring of the brain” following
neurological trauma, including stroke and traumatic brain injury.
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go to Clinical Program |
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