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BRaIN Imaging Center
Department of Neurology
MSC 10-5620
1 University of New Mexico
Albuquerque, NM 87131
Physical Address:
1101 Yale NE
Albuquerque, NM 87131
Phone
(505) 272-8182
Fax (505) 272-8306
Email:
jcordova@salud.unm.edu
Acknowledgement:
The construction of the wing housing BRaIN in Domenici Hall
was made possible with a grant from the NCRR (C06-RR107566).
The research at BRaIN is supported by several NIH grants
with a major funding from a center grant from the NCRR
(P20-RR15636).
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project 1. Honglian Shi |
project 2. Xinyu Zhao |
| project 3. Wolfgang Mueller (Müller) |
project 4. Surojit Paul |
| project 5. Mitsuhiro Morita |
Project 1:
Honglian Shi, Ph.D. - Graduated
Received R01 2008
Oxidative
stress results from the imbalance between free radical
production and the antioxidant cascade. The stress has
been implicated in the
process of aging and the pathogeneses of more than sixty
pathological conditions including stroke, heart disease,
cancers, and diabetes. Antioxidant
therapy has been trialed for treatments of stroke,
Alzheimer’s Diseases and other diseases. My
interests in antioxidant prevention and therapy lead me
to investigate free radical metabolism, to explore the
mechanisms of free radicals in a variety of diseases and
aging, to understand the interaction between free
radicals and antioxidants, and to find efficient and
specific treatments. Cerebral ischemia/reperfusion has
tremendous effect on free radical metabolism due to the
changes in the levels and metabolism of oxygen and
glucose. Glucose is not only a major energy source but
also a major supply of reducing agents, which plays a
very important role in maintaining cellular glutathione
level. The ongoing project is to understand the changes
of small redox metabolites such as glutathione, their
functions in regulating transcription factors, and their
roles in cell death and survival in ischemic conditions.
The interaction between reactive oxygen species, redox
status and HIF-1 expression is being pursued with
biochemical, biophysical, and molecular approaches.
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Upon focal ischemia in adult brains, a large
number of new cells migrate from the
subventricular zone (SVZ) to the injured
striatum, where they potentially participate in
neuronal regeneration. We have found that
inflammatory cytokines, such as IL-6 and IL-1β
can promote neuronal differentiation of adult
neural stem cells (see
Barkho et al 2006). We are currently
investigating how adult neural stem cells behave
in response to brain injuries and the underlying
molecular mechanisms. Our long-term goal is to
establish a molecular basis for utilizing adult
neurogenesis and adult neural stem cells in
brain repair. We are using a combination of cell
biology, molecular biology, and brain imaging
approaches in this project. This work is funded
by NIH/COBRE.
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Mesial temporal lobe epilepsy (TLE) is the most common type of epilepsy
in adults and can be caused by a variety of
insults. Specific loss of entorhinal cortex
(EC) Layer 3 (L3) pyramidal neurons (PNs) and
hyperexcitability of L5 PNs are characteristic
for early stages of the disease while damage
elsewhere, as in the hippocampus follows after
prolonged accumulation of seizures. This
projects studies the cellular and synaptic
changes that occur in the entorhinal cortex in
the early stages of TLE evolution, poorly
understood at present. The research utilizes the
pilocarpine model of TLE to examine early
mechanisms of EC L5 hyperexcitability. In this
model, status epilepticus (SE) is evoked in rats
by systemic application of the cholinergic-muscarinic
agonist pilocarpine and terminated after one
hour by benzodiazepines. After a silent period
of 2 – 4 weeks spontaneous seizures occur.
Resulting seizures (both pilocarpine-induced and
spontaneous) originate in EC-L5, and then spread
to L2 and on into the hippocampus. Pathologic
release of endogenous acetylcholine may also
initiate similar status epilepticus, as a
consequence of the dense cholinergic innervation
of all layers of the entorhinal cortex by
convergence of cholinergic fibers from the basal
ganglia, the forebrain nuclei and the septum.
Studies in this project test the hypothesis that deficiencies in synaptic
inhibition of EC-L5 pyramidal neurons cause TLE,
and address key mechanisms underlying EC-L5
hyperexcitability. Most studies compare
preparations from control and pilocarpine
treated rats 2 and 3 weeks after SE, to
determine a) changes in neuronal Cl--transporters
(compromising GABAergic synaptic inhibition), b)
vesicular release probability changes for
glutamatergic excitatory and GABAergic
inhibitory synaptic terminals, c) excitability
changes in neuronal synaptic networks due to
changes in synaptic efficacy and circuit
structure, and d) local disturbance in neuronal
[Ca2+]i-homeostasis
mechanisms as a trigger for cell death of L3
pyramidal neurons and loss of excitation to
inhibitory neurons. This issues are studied
using sharp electrode and patch clamp recording,
immunocytochemistry, two-photon laser scan
fluorescence microscopy of presynaptic vesicular
release and intracellular Ca2+-concentration
and diode-array imaging of excitability spread
in neuronal tissue.
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The mitogen activated protein kinases (MAPKs)
are expressed ubiquitously in the central
nervous system. They participate in diverse
physiological processes, including neuronal
maturation and survival, learning and memory as
well as neuronal cell death. Multiple lines of
evidence strongly indicate that MAPK pathways
are also involved in the pathophysiology of
alzheimer’s disease, parkinson’s disease,
schizophrenia and stroke. This raises the
questions as to how they can participate in such
diverse patho-physiological processes? Growing
evidence suggests that the magnitude and
duration of MAP kinase activation are important
in determining a particular biological outcome.
But how cells determine the duration of MAP
kinase signaling is still unclear. The fact that
MAPKs are activated by a single kinase but
inactivated by several phosphatases, indicate
that diverse signals are probably integrated at
the phosphatase level. The primary goal of our
laboratory is to elucidate the role of the
protein tyrosine phosphatases, STEP (striatal-enriched
tyrosine phosphatase) and PTP-SL (STEP like
tyrosine phosphatase) in the regulation of the
MAP kinase signaling pathways under different
patho-physiological condition.
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Neurotransmitter
receptor expression and dynamic intracellular calcium
behavior in astrocyte suggest this most abundant
non-excitable brain cell as an active component in neural
information processing. However, physiological dynamics of
calcium increase in astrocyte and its implication in brain
function and pathology are far from to be understood. Among
proposed consequences of neurotransmitter-induced and
spontaneous astrocyte calcium increase, exocytotic release
of neuromodulatory substances, so-called gliotransmitters,
including glutamate, ATP/adenosine, and D-serine, an
endogenous NMDA receptor glycine site agonist, and
subsequent tuning of brain activities is the most
fascinating model. Since astrocyte calcium increase
patterns, especially calcium oscillation is regulated by
brain environmental factors, such as neurotransmitter,
growth factor and cytokine, as reported in my previous
studies , the gliotransmitter release is assumed to be
affected by the same factors. Therefore local or global
brain environmental changes reflecting psychological
conditions such as mood and sleep, up-regulated neuronal
activities leading to memory formation and pathological
processes for neuronal degeneration, regeneration and
epilepsy, may affect neuronal activities by altering
astrocyte calcium dynamics and gliotransmitter release. Our
preliminary work using cell culture model suggests astrocyte
is equipped with multiple vesicular release machineries,
each of which is utilized for a distinct type of
gliotransmitter, triggered by specific calcium increase
pattern, and up-regulated by unique cell signaling. The
multiple release machineries may imply the brain
environmental factors affect both quantity and type of
gliotransmitter release, and astrocyte deciphers context for
appropriate gliotransmitter release. Our aim is to
characterize the molecular machineries for gliotransmitter
release, and to reveal the utilizations of gliotransmitters
in brain function and pathology. Since astrocyte is known to
be activated in aging and diverse brain pathologies,
gliotransmitter release is assumed to change in these
activation states, which again reflect brain environment.
Therefore, we believe this project will give rise to novel
approaches for age-dependent alteration of brain function,
and acute and progressive brain disorder. Now we are
focusing on astrocyte activations in traumatic brain injury,
which includes multiple types of astrocyte activation,
changes neuronal population and synaptic connectivity, and
leads to neurodegeneration and epilepsy. For this purpose,
we employ imaging techniques for calcium and vesicular
release in cell culture, brain slice and in vivo preparation
by high sensitive camera and two photon microscope, as well
as molecular biological analysis.
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