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Huangui Xiong, MD, PhD
Ongoing Projects:
1. Examination of soluble factors released by HIV-1-infected or
Aβ-stimulated mononuclear phagocytes (MPs, brain macrophages
and microglia) on cellular and synaptic physiology
We are interested
in determining how soluble factors released from HIV-1-infected
or Aβ-stimulated MPs affect cellular and synaptic
functions. Particularly, we examine the effects of HIV-1-infected
or Aβ-stimulated human monocyte-derived macrophage (MDM) conditioned
media or specific viral and/or immune factors on neuronal biophysical
and electrophysiological properties, and on synaptic transmission
and plasticity in the hippocampus. We hypothesize that MP-secretions
alter neuronal electrophysiological processes and modulate synaptic
transmission and plasticity. How HIV-1-infected MPs affect neuronal
and synaptic functions is a main focus of this project.
2. Characterization
of soluble factors secreted from HIV-1-infected and/or Aβ-stimulated
MPs on NMDA receptors expressed on Xenopus oocytes.
A second interest
in our laboratory is to explore the molecular mechanisms underling
MP-mediated neurotoxic activities. As neuronal damages induced
by HIV-1-infected or Aβ-stimulated MPs could
be prevented or attenuated by NMDA receptor antagonists we are
interested in determining whether the soluble factors secreted
by HIV-1-infected or Aβ-stimulated MPs act directly on NMDA
receptors. Thus, whether MP secretory factors activate specific
subtype NMDA-receptors is under investigation. Our studies focus
on NMDA receptor subtypes NR1/NR2A and NR1/NR2B expressed on Xenopus
oocytes using two-electrode voltage clamp and single channel recording
techniques. It is our hypothesis that activation of specific subtype(s)
of NMDA receptors represents common mechanisms for MP-mediated
neuronal dysfunction or injury.
3. Investigation on how HIV-1-infecetd macrophages affect neuronal
function in a macrophage-neuronal co-culture system.
Recent studies
have provided compelling evidence that neuronal voltage-gated
K channels (Kv) play an important role in memory processes and
acquired neuronal channelopathies in HAD. It has been demonstrated
on different model systems that K currents decrease during learning
and that Kv channel antagonists improve learning and memory. We
are interested in exploring how macrophages affect neuronal voltage-gated
K channels. We hypothesize that HIV-1-infected MPs alter neuronal
Kv channel activity. This may be achieved through direct MP-neuron
contact, and/or through paracrine amplification of MP-secreted
toxins or both, leading to neuronal dysfunction. Our goal is to
understand the role of Kv channels in MP-mediated neuronal dysfunction
and its association with MP toxin production.
4. Determination of
how MP-associated alterations in cellular and synaptic functions
occur in an animal model of HIV-1-encephalitis (HIVE).
The bridge
between our laboratory studies and their relevance for disease
is made in animal models of HIVE. In this way we can assess how
alterations in cellular and synaptic functions occur by MP secretory
factors in vivo. We use a severe combined immunodeficient (SCID)
mousemodel of HIVE to study how virus infected and immune competent
brain MP effect neuronal function. Our goal is to determine if
the results uncovered in laboratory models relate to neuronal
electrophysiological changes seen in the HIVE animals. This entails
integrative ex vivo electrophysiological and neuropathological
investigations. Electrophysiological and behavior studies are performed
in tandem to address how cognitive abnormalities in HIVE SCID mice
may predict alterations in neurophysiology and neuropathology and
vice versa during disease.
Recent Publications:
Zheng, J., Thylin, M. R., Ghorpade, A., Xiong, H., Cotter, R.,
Niemann, D., Che, M., Zeng, Y., Shepard, R. B., Swartz, J.M., Persidsky,
Y., Gendelman, H. E. Intracellular CXCR4 Signaling, Neuronal Apoptosis,
and the Neuropathogenic Mechanisms for HIV-1-associated Dementia.
J. Neuroimmunol. 98: 185-200, 1999.
Xiong, H., Li, C., Garami, E., Wang, Y., Ramjeesingh, M., Galley,
K. and Bear, C. ClC-2 activation modulates regulatory volume decrease.
J. Membrane Biology 167: 215-221, 1999.
Xiong, H., Zheng,J., Thylin M., and Gendelman, H.E. Unraveling
the mechanisms for neurotoxicity in HIV-1 associated dementia:
Inhibition of neuronal synaptic transmission by macrophage secretory
products. AIDS Res. Hum. Retrov. 15 (1): 57-63, 1999.
Xiong, H., Zeng, Y.C., Zheng, J., Thylin, M. and Gendelman, H.E.
Soluble HIV-1 infected macrophage secretory products mediate blockade
of long-term potentiation: a mechanism for cognitive dysfunction
in HIV-1-associated dementia J. NeuroVirol. 5:519-528, 1999.
Xiong, H., Y-C Zeng, T. Lewis, J. Zheng, Y. Persidsky and H.E.
Gendelman HIV-1 infected mononuclear phagocyte secretory products
affect neuronal physiology: relevance for HIV-1-associated dementia.
J. NeuroVirol. 6:S14-S23, 2000.
Zheng, J., Thylin, MR, Cotter, R., Lopez, AL, Ghorpade, A., Persidsky,
Y., Xiong, H., Leisman, GB, Che, MH and Gendelman, HE . HIV-1 infected
and immune competent mononuclear phagocytes induce quantitative
alterations in neuronal dendritic arbor: Relevance for HIV-1-associated
dementia. Neurotoxicity Res. 3:443-459, 2001
Zink, W.E., Boyle, J. Persidsky Y, Xiong, H. and Gendelman, H.E.
Model system for assessing cognitive function: implication for
HIV-1 infection and drugs of abuse. In: Neuroimmune Circuits, Drugs
of Abuse and Infectious Diseases, eds. John Madden, Thomas Klein
and Herman Friedman, Kluwer Academic/Plenum Publishers. pp. 7-27,
2001.
Zink, W., Anderson, E., Boyle, J., Hock, L., Rodriguez-Sierra,
J., Xiong, H., Gendelman, H.E. and Persidsky,Y. Impaired Spatial
Cognition and Synaptic Potentiation in a Murine Model of HIV-1
Encephalitis. J. Neurosci. 22(6):2096-2105, 2002.
Anderson, E., Zink, W., Xiong, H. and Gendelman, H.E. HIV-1-Associated
Dementia: A Metabolic Encephalopathy Perpetrated by Virus-Infected
and Immune Competent Mononuclear Phagocytes. J. AIDS 31:S43-S54,
2002.
Xiong, H. Boyle, J. Persidsky, Y. Carlson, K. Zheng, J. Ghorpade,
A. and Gendelman, H.E. Inhibition of Long-term Potentiation by
Interleukin-8: Implications for HIV-1-associated Dementia. J. Neurosci.
Res. 71:600-607, 2003.
Anderson, E.R., Boyle, J., Zink, W.E. Persidsky, Y., Gendelman,
H.E. and Xiong. H. Hippocampal Synaptic Dysfunction in a Murine
Model of HIV-1 Encephalitis. Neuroscience 118(2):359-369, 2003
Xiong, H., McCabe, L., Skifter, D., Monaghan, D.T. and Gendelman,
H.E. Activation of NR1a/NR2B receptors by monocyte-derived macrophage
secretory products: Implications for human immunodeficiency virus
type one-associated dementia. Neurosci. Lett. 341(3):246-250, 2003.
Ikezu, T., Luo, X. Zhao, J., McCabe, L., Ghorpade, A., Zheng,
J., Weber, G. Xiong, H. Amyloid precursor protein-processing products
affect mononuclear phagocyte activation: Pathways for sAPP and
Aβ mediated neurotoxicity. J. Neurochemistry 85(4):925-934,
2003.
Shibata, A., Zelivyanskaya, M., Limoges, J., Carlson, K., Gorantla,
S., Branecki, C., Bishu, S., Xiong, H., and Gendelman, H.E. Peripheral
nerve induces macrophage neurotrophic activities: regulation of
neuronal process outgrowth, intracellular signaling and synaptic
function. J. Neuroimmunology 142:112-129, 2003
Anderson, E. Ryan, L. Xiong, H., Swindells, S., Zheng, J. and
Gendelman, H.E. Neural Immunity and HIV-1-Associated Dementia,
in “Blood-Spinal Cord and Brain Barriers in Health and Disease” edited
by Hari Shanker Sharma and Jan Westman. Elsevier Inc. pp.547-559,
2004.
Xiong, H., McCabe, L., Castello, K., Anderson, E., Weber, G.,
and Ikezu, T. Activation of NR1a/NR2B receptors by secretory products
from APP-stimulated monocyte-derived macrophages: Implications
for the pathogenesis of Alzheimer’s Disease. Neurobiology
of Aging 25(7):905-911, 2004.
Anderson, E.R., Gendelman, H.E. and Xiong, H. Memantine Protects
Hippocampal Neuronal Function in a Murine Model of HIV-1 Encephalitis.
J. Neurosci. 24(32):7194-7198, 2004.
Anderson, E.R. Xiong, H. and Gendelman, H.E. Animal model systems
of HIV-1 associated disease. In “Animal Models of HIV Disease” edited
by Herman Friedman, Kluwer Pub. (In Press)
Nelson, J.A., Dou, H., Boska, M., Ellison, B. Uberti, M., Xiong,
H., Anderson, E.R., Mellon, M., Gelbard, H.A. and Gendelman, H.E.
Co-registration of quantitative proton magnetic resonance spectroscopic
imaging with neuropathological and neurophysiological analyses
defines the extent of neuronal impairments in murine HIV-1 encephalitis.
J. Neurosci. Res. (in Press).
ACTIVE GRANTS
1. Source: NIH NINDS 1RO1 NS41862-04
Title: Neuronal Physiology and HIV-1 Associated Dementia
PI: Huangui Xiong, 50% of effort
Annual direct cost: $125,000
Dates: 06/15/01–05/31/05
2. Source: NIH NINDS 3R01 NS41862-02S1
Title: Neuronal Physiology and HIV-1 Associated Dementia - Minority
Supplement
PI: Huangui Xiong (investigator: Eric Anderson)
Annual cost: $20,145
Dates: 09/01/03 – 08/31/04
3. Source: NIH NINDS 2R37 NS36126
Title: Blood-brain Barrier Physiology and HIV Dementia
Co-I: Huangui Xiong (PI, Dr. Gendelman), 17% of effort
Annual direct cost: $250,000
Dates: 12/1/01-3/31/08
4. Source: NIH NINDS R01 NS 41858-04
Title: Macrophage Activation, Chemokines, and HIV Dementia
Co-I: Huangui Xiong (PI, Dr. Jialin Zheng), 7% of effort
Annual direct cost: $175,000
Dates: : 06/01/01 - 05/31/05
5: Source: NIH NINDS R01 NS43113-03
Title: Astrocyte activation, Fas ligand, and HIV-1 dementia
Co-I: Huangui Xiong (PI, Dr. Anuja Ghorpade), 5% of effort
Annual direct cost: $142,000
Dates: : 12/01/01-11/30/06
6. Source: NIH NINDS 1T32 NS07488
Title: Training Program in Neurovirology (Neuroscience Research
Training Program)
NRTP Trainer: Huangui Xiong (PI, Dr. Gendelman)
Annual direct cost: $119,630
Dates: 7/1/02-6/30/07
7. Source: NIH NINDS P01NS43985-01
Title: Neural Immunity in HIV Dementia (Projects 2 &3)
Co-I: Huangui Xiong (PI, Dr. Gendelman)
Annual direct cost: $66,240
Dates: 5/15/03-4/30/08
8. Source: Department of Pharmacology/PEPR Program
Title: NR2B-containing NMDA receptors and HIV-1 associated dementia
PI: Huangui Xiong
Annual direct cost: $30,000
Dates: 1/03/05-12/31/05
9. Source: NSF/MRSEC (UNL internal competition)
Title: Piezo-micromanipulation
Co-PI: Huangui Xiong (PI, Dr. Benard Doudin)
Annual direct cost: $ 17,670
Dates: 2/01/04 - 4/30/05
Pending:
1. Source: NIH NINDS 1 R01 NS050086-01
Title: Mononuclear Phagocytes, NMDA receptor and HIV dementia
PI: Huangui Xiong
Annual direct cost: $250,000
Dates: 07/01/04 – 06/30/09
2. Source: NIH NINDS 2 R01 NS 41862-05
Title: Macrophages, Neuronal K channels and HIV dementia
PI: Huangui Xiong
Annual direct cost: $225,000
Dates: 07/01/05 – 06/30/10
3. Source: NIH NINDS 1 R01
Title: SDF-1 Proteolysis, Neurogenesis and HIV-1 dementia
Co-I: Huangui Xiong (PI: Dr. Jialin Zheng)
Annual direct cost: $250,000
Dates: 07/01/04 – 06/30/09
4. Source: NSF
Title: Development of New Interdisciplinary Applications of Laser
Scanning Microscope
Co-I: Huangui Xiong (PI: Dr. Benard Doudin, UNL)
Annual direct cost: $180,829
Dates: 7/01/04 - 6/30/06
Completed Grants:
1. Source: NIH P20 RR15635-01
Title: Nebraska Center for Viral Pathogenesis (COBRE)
Co-I: Huangui Xiong (PI: Dr. Charles Wood, UNL)
Annual direct cost: $199,657
Dates: 10/01/00 - 09/30/2001
2. Source: NIH NINDS R01 NSA136127-01
Title: Neuronal Electrophysiology in HIV-dementia
Co-I: Huangui Xiong (PI: Dr. Gendelman)
Annual direct cost: $227.20
Dates: 9/1/98 - 4/30/03
3. Source: NIH NINDS 3 RO1 NS41862-02S2
Title: Neuronal Physiology and HIV-1 Associated Dementia – supplement
PI: Huangui Xiong
Annual direct cost: $17,000
Dates: 09/1/02 – 08/31/03
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