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. Selected Recent Publications: 1. Wang, WW, Hu, DH. Xiong, H. Macrophage attenuation of neuronal excitability: Implications for pathogenesis of neurodegenerative disorders. Glia 2007. 2. Kasiyanov, A. Tamamura, H. Fujii, N. Xiong, H. Modulation of network-driven, GABA-mediated giant depolarizing potentials by SDF-1a in developing hippocampus. Develop. Neurosci., 2007. 3 Xiong, H. Hippocampus and Neuroimmunity. In “neuroimmunee Pharmacology” edited by Ikezu, T. and Gendelman, H.E., Springer publishers, 2007. 4. Lewitus, GM, Zhu,J. Warren, T. Xiong, H. Hallworth,R. and Kipnis, J. Depletion of CD4+CD25+ Regulatory T Cells Results in Inhibition of Hippocampal Long-Term Potentiation by CD4+ T Cells. Eur. J. Neurosci. 26(6):1399-1406, 2007. 5. Irvine, E. Keblesh, J. Liu, J. Xiong, H. Voltage-gated potassium channel modulation of neurotoxic activity in human immunodeficiency virus type-1(HIV-1)-infected macrophages. J Neuroimmune Pharm. 2(3):265-269, 2007. 6. Li, L., Yun, SH., Keblesh, J., Barbara L. Trommer, BL., Xiong, H., Radulovic, J., Tourtellotte, WG Egr3, a synaptic activity regulated transcription factor that is essential for learning and memory. Mol. Cell. Neurosci 35(1):76-88, 2007. 7. Dong, J. and Xiong, H. HIV-1gp120 inhibits long-term potentiation through CXCR4 in the rat hippocampus. J. Neurosci. Res. 83:489-498, 2006. 8. Kasiyanov, A. Tamamura, H. Fujii, N. Xiong, H. HIV-1gp120 enhances giant depolarizing potentials via chemokine receptor CXCR4 in neonatal rat hippocampus. Eur. J. Neurosci. 23:1120-1128, 2006. 9. Dou, H., Ellison, B., Bradley, J., Kasiyanov, A., Xiong, H., Maggirwar, S., Dewhurst, S., Gelbard, H.A. Gendelman, H.E. Lithium induces neuroprotective activities in murine HIV-1 encephalitis. J. Neurosci. 25(37), 2005. 10. 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. 80(4):562-75, 2005. 11. 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. 2005. 12. Anderson, E.R., Gendelman, H.E. and Xiong, H. Memantine Protects Hippocampal Neuronal Function in a Murine Model of HIV-1 Encephalitis. J. Neurosci. 24:7194-7198, 2004. ACTIVE GRANTS 1. Source: NIH NINDS 1RO1 NS41862-04 2. Source: NIH NINDS 3R01 NS41862-02S1 3. Source: NIH NINDS 2R37 NS36126 4. Source: NIH NINDS R01 NS 41858-04 5: Source: NIH NINDS R01 NS43113-03 6. Source: NIH NINDS 1T32 NS07488 7. Source: NIH NINDS P01NS43985-01 8. Source: Department of Pharmacology/PEPR Program 9. Source: NSF/MRSEC (UNL internal competition) Pending: 2. Source: NIH NINDS 2 R01 NS 41862-05 3. Source: NIH NINDS 1 R01 4. Source: NSF Completed Grants: 1. Source: NIH P20 RR15635-01 2. Source: NIH NINDS R01 NSA136127-01 3. Source: NIH NINDS 3 RO1 NS41862-02S2 |
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