We propose that the role played by mononuclear phagocytes (MP;microglia, perivascular and brain macrophage) in the neuropathogenesis of H1V-1 infection can be harnessed for therapeutic benefit. The work will be conducted in the Department of Pharmacology and Experimental Neuroscience at the University of Nebraska Medical Center (UNMC). The department is a result of the merger of the Center of Neurovirology and Neurodegenerative Disorders (CNND) and the UNMC Department of Pharmacology. The fusion of the two created a Neuroscience Program with one director, Howard E. Gendelman, significantly improved the program project scientific infrastructure. Indeed, the disciplines of neuroscience, immunology, and pharmacology are integrated as a result of the CNND's evolution since its formation in 1997. Ongoing collaborations in stem cell biology, neuropharmacology, virology, blood-brain barrier biology, proteomics, bioimaging, and molecular neuroscience are now operative and an integral part of this proposal. Links between intracellular processes, microglial activation, and neuronal degeneration provided opportunities to harness immune responses for therapeutic benefit. The proposal includes three projects that center around MP pathobiology including: neural progenitor stem cell mobility and function in laboratory and animal models of NeuroAIDS (project, 1, J. Zheng);a blood-borne monocyte derived-macrophage-based nanoparticle delivery of anti-retroviral drugs in NeuroAIDS (project 2, H. Gendelman);and studies of the molecular, biochemical, and cell biologic consequences to the blood-brain barrier and viral neuropathogenesis in laboratory and animal models of human disease (project 3, Y. Persidsky). The cores include: cell biology and brain tissue collections (core A, T. Ikezu), bioimaging (core B, M. Boska), proteomics (core C, P. Ciborowski), and an administrative oversight (core D, H. Gendelman). Each project/core will support, enhance, and provide interdisciplinary research that will enhance the quality of the works and the opportunities for cross-validation of experimental results and success. Taken together, the program has matured, is focused, productive, and synergistic. All the resources, techniques, and models are in place to permit the necessary opportunities for significant contributions to the field.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Program Projects (P01)
Project #
5P01NS043985-10
Application #
8231499
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Program Officer
Wong, May
Project Start
2002-04-01
Project End
2014-02-28
Budget Start
2012-03-01
Budget End
2014-02-28
Support Year
10
Fiscal Year
2012
Total Cost
$1,131,457
Indirect Cost
$466,035
Name
University of Nebraska Medical Center
Department
Pharmacology
Type
Schools of Medicine
DUNS #
168559177
City
Omaha
State
NE
Country
United States
Zip Code
68198
Zhang, Gang; Guo, Dongwei; Dash, Prasanta K et al. (2016) The mixed lineage kinase-3 inhibitor URMC-099 improves therapeutic outcomes for long-acting antiretroviral therapy. Nanomedicine 12:109-22
Dong, Weiguo; Embury, Christine M; Lu, Yaman et al. (2016) The mixed-lineage kinase 3 inhibitor URMC-099 facilitates microglial amyloid-β degradation. J Neuroinflammation 13:184
Guo, Dongwei; Zhou, Tian; Araínga, Mariluz et al. (2016) Creation of a Long-Acting Nanoformulated 2',3'-Dideoxy-3'-Thiacytidine. J Acquir Immune Defic Syndr :
Araínga, Mariluz; Su, Hang; Poluektova, Larisa Y et al. (2016) HIV-1 cellular and tissue replication patterns in infected humanized mice. Sci Rep 6:23513
Olson, Katherine E; Gendelman, Howard E (2016) Immunomodulation as a neuroprotective and therapeutic strategy for Parkinson's disease. Curr Opin Pharmacol 26:87-95
Olson, Katherine E; Bade, Aditya N; Schutt, Charles R et al. (2016) Manganese-Enhanced Magnetic Resonance Imaging for Detection of Vasoactive Intestinal Peptide Receptor 2 Agonist Therapy in a Model of Parkinson's Disease. Neurotherapeutics 13:635-46
Li, Weizhe; Tong, Hsin-I; Gorantla, Santhi et al. (2016) Neuropharmacologic Approaches to Restore the Brain's Microenvironment. J Neuroimmune Pharmacol 11:484-94
Singh, Dhirender; McMillan, JoEllyn; Hilaire, James et al. (2016) Development and characterization of a long-acting nanoformulated abacavir prodrug. Nanomedicine (Lond) 11:1913-27
Sajja, Balasrinivasa R; Bade, Aditya N; Zhou, Biyun et al. (2016) Generation and Disease Model Relevance of a Manganese Enhanced Magnetic Resonance Imaging-Based NOD/scid-IL-2Rγc(null) Mouse Brain Atlas. J Neuroimmune Pharmacol 11:133-41
Bade, Aditya N; Gorantla, Santhi; Dash, Prasanta K et al. (2016) Manganese-Enhanced Magnetic Resonance Imaging Reflects Brain Pathology During Progressive HIV-1 Infection of Humanized Mice. Mol Neurobiol 53:3286-97

Showing the most recent 10 out of 218 publications