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Dennis
L. Kolson, MD, PhD
Associate Professor,
Depts of Neurology and Microbiology
Microbiology,
Virologyand Parasitology Program
Address
280C Clinical Research Building (Lab)
415 Curie Boulevard
Philadelphia, PA 19104
Office tel.: 215 573-3505
Lab tel.: 215 573-3504
Fax: 215 573-2029
E-mail: kolsond@mail.med.upenn.edu
Education
Pennsylvania State University: BS (Biology), 1977.
University of Pittsburgh: MS (Biological Sciences), 1980.
University of Pittsburgh: PhD (Biological Sciences), 1984.
University of Pittsburgh School of Medicine: MD (Medicine), 1985.
Duke University: Residency (Neurology), 1989.
University of Pennsylvania: Postdoctoral Research (Neurology/Microbiology).
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Research
Interests
- Mechansims and determinants of HIV induced
neuronal injury. Neuronal cell responses to virus induced
injury.
Key words: neuron, hippocampus, apoptosis,
gene expression, single-cell mRNA, HIV, chemokine receptor,
NMDA receptor.
Search PubMed for articles
Description
of Research
My laboratory is focused upon pathogenesis of
HIV-1-infection of the central nervous system (CNS). We utilize
techniques of single-cell microdissection and mRNA expression
analysis, and standard molecular biological approaches in
our unique in vitro model to study mechanisms of neurodegeneration
caused by HIV. Within the CNS, HIV productively infects macrophages
and microglia, with subsequent neuronal loss by apoptosis.
In vitro modeling shows that such infection results in the
release of soluble neurotoxins that act in part through activation
of neuronal NMDA receptors with subsequent activation of cell
death pathways, including apoptosis cascades and calpain activation.
Specific NMDA receptor subunits (NR2A, NR2B) are critical
for such degeneration. In addition, dysregulation of glial
(astrocyte, macrophage) neurotransmitter and oxidative functions
may subserve both apoptotic and anti-apoptotic roles. Major
unanswered questions include:
- What pathways are reponsible for neuronal apoptosis/damage
and glial cell dysfunction in HIV infection?
- How can NMDA receptor modulation alter neuronal susceptibility
to HIV-induced damage?
- Are specific genes turned on/off in neurons that are
particularly vulnerable/resistant to HIV-induced injury?
- What is the role of endogenous neuronal survival pathways
in preventing HIV-induced damage?
- How can in vitro modeling be used to define targets for
neuroprotection against HIV-1?
- How can single-cell mRNA analysis be used to define patterns
of gene expression in the brain to define mechanisms of
neuronal death/damage and survival that may identify unique
targets for neuroprotective strategies against HIV?
To address these questions, we have developed
several in vitro neuronal cell culture systems. We utilize
primary rodent hippocampal and neocortical cell cultures as
well as a unique human neuronal cell system utilizing NT2.N
neurons in mixed neuronal/glial cell cultures to model HIV-1-induced
neurodegeneration. We have developed a novel in vitro model
using mixed cultures of human monocyte-derived macrophages
with rodent neurons and astrocytes to analyze effects of HIV
infection in the central nervous system. We have found that
developmental susceptibility to HIV-1-induced neurodegeneration
is determined by NMDA receptor subunit expression, and that
the macrophage kynurenine metabolic pathway is a major contributor
to the production of HIV-1-induced excitotoxin expression.
We have utilized single-cell microdissection and mRNA expression
analyses to develop gene expression profiles in individual
neurons in archival human brain and in cell cultures. Our
current projects involve in vitro and in vivo analysis of
cell death pathways in neurons that are induced by HIV-infected
macrophages, analysis of the role of specific NMDA receptor
subunits in determining neuronal vulnerability to HIV-induced
damage, analysis of the modulation of the kynurenine metabolic
pathway in macrophages by HIV-1, and in vitro analysis of
neuronal gene expression in hippocampal and neocortical cell
cultures through single-cell mRNA analysis.
Recent
Publications
O’Donnell L, Agrawal A, Jordan-Sciutto
K, Dichter M, Lynch D and Kolson DL. (2006). HIV-induced neurotoxicity:
roles for the N-methyl-D-aspartate receptor subtypes 2A and
2B, and the calcium activated protease calpain by a cerebrospinal
fluid-derived HIV-1 strain. J. Neurosci. 26: 981-990.
Ances BM, Roc AC, Wang J, Korczykowski M, Okawa
J, Stern J, Kim J, Wolf R, Lawler K, Kolson DL, Detre JA.
(2006). Reduced cerebral blood flow and volume in the caudate
of HIV neurocognitively impaired patients. Neurology
66: 862-866.
Sui Y, Stehno-Bittel L, Shanping L, Loganathan
R, Dhillon NK, Pinson D, Nath A, Kolson D, Narayan O, Buch
S. (2006). CXCL-10-induced cell death in neurons: role of
calcium dysregulation. Eur J Neurosci. 2006 Feb;23(4):957-64.
Kolson DL, Sabnekar P, Baybis M and Crino PB.
(2004). Gene expression in TUNEL-positive Neurons in HIV-infected
brain. J. Neurovirol. 10(suppl. 1): 102-7.
Chen W, Sulcove J, Frank I, Jaffer S, Ozdener
H and Kolson DL. (2002). Development of a human neuronal cell
model for HIV/macrophage-induced neurotoxicity: apoptosis
induced by HIV-1 primary isolates and evidence for involvement
of the Bcl-2/Bcl-xL-sensitive intrinsic apoptosis pathway.
J. Virology 76: 9407-9419.
Lab
Rotation
Projects for 2006-2007
- Analysis of NMDA receptor subunit expression
and phosphorylation patterns in hippocampal and cortical
neurons susceptible to HIV neurotoxicity
- Analysis of neuronal gene expression,in HIV-injured
hippocampal and neocortical cells utilizing single-cell
microdissection and mRNA analysis.
- Identification of the downstream pathways
of death in neurons by HIV-1, including the role of calpain
activation.
- Lab
personnel:
- Praveena Sabnekar, PhD - Research Specialist
Lorraine Kolson, BS - Research Specialist
Rebecca Chodroff, BS - Research Specialist
Lauren O'Donnell - CAMB Graduate student
Stephan Kadauke – CAMB MD/PhD student
Summer 2006 Rotation Students:
Tammy Slenn, University of Richmond
Michael Lieberman, University of Pennsylvania
Ravi Gupta, Johns Hopkins University
last updated 6/2006
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