Huanyu Dou, MD

Instructor University of Nebraska Medical Center Department of Pharmacology and Experimental Neuroscience 985880 Nebraska Medical Center Omaha, NE 985215 Ph: 402-559-8925 Fax: 402-559-3744

Current Research

1. Determination of how HIV-1 infected MP-associated neurotoxicity alterations in cellular and functions occur in an animal model of HIV-1-encephalitis (HIVE). Our investigations are designed to study the mechanisms and neurotoxic activities for HAD. Although a range of cell-signaling pathways affect neuronal function in HAD, the GSK-3b pathway, in particular, is a major contributor to neurotoxic outcomes. GSK-3b pathway potentially has neuroprotective activity in HIV-1 associated neuronal injury. GSK-3b inhibitors testing for neuroprotective in severe combined immunodeficient SCID mice with HIVE. used for designing adjunctive therapeutic strategies for treatment and/or prevention of neuronal degeneration following HIV-1 infection. In this regard, the studies focus to test neuroprotective drugs developing in laboratory assays in a SCID mouse model of HIVE. This studies are based on a reversible metabolic encephalopathy caused by defective immunity of virus-infected MP which serve both as reservoirs for productive HIV-1 infection and principal sources of neurotoxic activities within the central nervous system. Moreover, we are also exploring the mechanisms through GSK-3b inhibitors against MP secretes neurotoxin.

2. To study the cellular mechanisms of astrocyte and microglia in neuroprotection and neurotoxicity defines the tempo of neuronal dysfunction during HIV-1-associated dementia (HAD). We focus that viral infection of astrocytes provides novel insights into the subtle neurodegenerative processes in a SCID mice model.

3. To develop monocytes/macrophage nano-medicine delivery system in a SCID mouse human immunodeficiency virus type one (HIV-1) encephalitis (HIVE) model. Ongoing efforts are designed to determine how macrophage nano-drugs delivery system improve anti-retroviral efficacy in a small animal model system of HIV-1 infection and viral encephalitis. Aim 1: Investigating Indinavir-loaded nanosuspensions can elicit antiviral activity when inoculated into human monocyte-derived macrophage (MDM) in laboratory models of disease. Aim 2: ultimating macrophages, containing the nanosuspension, traffic into tissue sites where active viral replication continues despite the advent of innate and adaptive immune responses elicited following HIV infection. Tracking systems will be developed to monitor monocyte and macrophage transport across the blood brain barrier, as well as, distribution to splenic, lymph node, liver, lung, and intestinal tissues. This will utilize Feridex as a labeling method for the elucidation of both anatomical structure and MP transport via magnetic resonance imaging (MRI). Indium labeling was subsequent imaging by the Angular Single Photon Emission Computed Tomography (A-SPECT) to visualize macrophage migration and distribution, as well. Lipopolysaccharide (LPS) will be injected into specific brain regions of normal mice to initiate the inflammatory process that would reflect HIV infection of the nervous system. Following LPS injection, labeled macrophages and monocytes will be monitored for brain entry using MRI and A-SPECT. Aim 3: investigating the effectiveness of the indinavir-nanosuspension both in vitro and in vivo. Aim 4: testing the efficiency of the nanoparticle carrier system specific transport of antiviral agents within the macrophage in an HIV-1 mouse model of human disease

Current Publications:

• Dou H, Ellison H, Bradley J, Kasiyanov A, Poluektova L, Xiong H, Maggirwar S, Dewhurst S, Gelbard HA, and Gendelman HE. Neuroprotective mechanisms of lithium in murine HIV-1 encephalitis. J Neurosci, 2005 Sep 14;25(37):8375-85.

• Potula R, Poluektova L, Knipe B, Chrastil J, Heilman D, Dou H, Takikawa O, Munn DH, Gendelman HE, Persidsky Y. Inhibition of Indoleamine 2,3-dioxygenase (IDO) enhances elimination of virus-infected macrophages in animal model of HIV-1 encephalitis. Blood. 2005 Jun 16.

• Dou H*, Ellison B, Uberti M, Xiong H, Anderson E, Mellon M, Gelbard HA, Boska M, Gendelman HE. Coregistration of quantitative proton magnetic resonance spectroscopic imaging with neuropathological and neurophysiological analyses defines the extent of neuronal impairments in murine human immunodeficiency virus type-1 encephalitis. Nelson JA*, J Neurosci Res. 2005 May 15;80(4):562-75.

• Dou H, Kingsley JD, Mosley RL, Gelbard HA, Gendelman HE. Neuroprotective strategies for HIV-1 associated dementia. Neurotox Res. 2004;6(7-8):503-21.

• Poluektova L, Gorantla S, Faraci J, Birusingh K, Dou H, Gendelman HE.Neuroregulatory events follow adaptive immune-mediated elimination of HIV-1-infected macrophages: studies in a murine model of viral encephalitis. J Immunol. 2004 Jun 15;172(12):7610-7.

• Boska MD, Mosley RL, Nawab M, Nelson JA, Zelivyanskaya M, Poluektova L, Uberti M, Dou H, Lewis TB, Gendelman HE. Advances in neuroimaging for HIV-1 associated neurological dysfunction: clues to the diagnosis, pathogenesis and therapeutic monitoring. Current HIV research, 2004, 2:61-78

• Dou H, Birusingh K, Faraci J, Gorantla S, Poluektova LY, Maggirwar SB, Dewhurst S, Gelbard HA, Gendelman HE. Neuroprotective activities of sodium valproate in a murine model of huma immunodeficiency virus-1 encephalitis. J Neurosci. 2003 Oct 8; 23(27):9162-70.

• Greenbaum L, Katcoff DJ, Dou H, Gozlan Y, Malik Z. A porphobilinogen deaminase (PBGD) Ran-binding protein interaction is implicated in nuclear trafficking of PBGD in differentiating glioma cells. Oncogene. 2003 Aug 14; 22(34): 5221-8.