Neurologic manifestations of HIV infection show deficits in cognitive and motor functions. Central nervous system (CNS) pathology underlying these clinical events include myelin pallor, macrophage/microglial activation, profound reactive gliosis and neuronal dropout. Interestingly, a progressive neuronal loss occurs without (to any significant degree) direct neural cell infection. Our laboratory has dedicated itself towards understanding how secretory products from immune activated HIV- I-infected macrophage/microglia produce progressive viral-associated neuropathology. Our initial work uncovered a large number of macrophage secretory products (toxins) likely involved in such neuronal damage. These include, but are not limited to, eicosanoids, proinflammatory cytokines, platelet activating factor, free radicals and excitatory amino acids (including cysteine and quinolinic acid). The specific mechanism(s) responsible for neuronal loss have not as yet been identified. In this application, we will extend our works by investigating macrophage secretions and its associated neurotoxicity to: 1) utilize """"""""state-of-the-art"""""""" electrophysiological methodologies to determine neuronal physiologic alterations following exposure to monocyte secretory products; 2) determine how pharmacological and/ or immunological manipulations of neurotoxic pathways can be prevented or reversed during HIV- I CNS infections; 3) characterize the electrophysiological basis for neuronal injury in our SCID mouse model of HIV encephalitis. In all works, the electrophysiological analyses will Include detailed patch clamp recording techniques to assess both synaptic and voltage-gated ion channels. Using this approach we intend to develop greater understanding for how secretory products from immune activated HIV- I- infected monocytes induce neuronal injury associated with progressive cognitive and motor dysfunctions seen in HIV-affected subjects.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS036127-03
Application #
2892212
Study Section
AIDS and Related Research Study Section 3 (ARRC)
Program Officer
Kerza-Kwiatecki, a P
Project Start
1997-04-01
Project End
2002-03-31
Budget Start
1999-04-01
Budget End
2000-03-31
Support Year
3
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Nebraska Medical Center
Department
Pathology
Type
Schools of Medicine
DUNS #
City
Omaha
State
NE
Country
United States
Zip Code
68198
Guo, Dongwei; Li, Tianyuzi; McMillan, JoEllyn et al. (2014) Small magnetite antiretroviral therapeutic nanoparticle probes for MRI of drug biodistribution. Nanomedicine (Lond) 9:1341-52
Epstein, Adrian A; Narayanasamy, Prabagaran; Dash, Prasanta K et al. (2013) Combinatorial assessments of brain tissue metabolomics and histopathology in rodent models of human immunodeficiency virus infection. J Neuroimmune Pharmacol 8:1224-38
Martinez-Skinner, Andrea L; Veerubhotla, Ram S; Liu, Han et al. (2013) Functional proteome of macrophage carried nanoformulated antiretroviral therapy demonstrates enhanced particle carrying capacity. J Proteome Res 12:2282-94
Nowacek, Ari; Kadiu, Irena; McMillan, JoEllyn et al. (2013) Immunoisolation of nanoparticles containing endocytic vesicles for drug quantitation. Methods Mol Biol 991:41-6
Puligujja, Pavan; McMillan, Joellyn; Kendrick, Lindsey et al. (2013) Macrophage folate receptor-targeted antiretroviral therapy facilitates drug entry, retention, antiretroviral activities and biodistribution for reduction of human immunodeficiency virus infections. Nanomedicine 9:1263-73
Stone, David K; Kiyota, Tomomi; Mosley, R Lee et al. (2012) A model of nitric oxide induced ?-synuclein misfolding in Parkinson's disease. Neurosci Lett 523:167-73
Kadiu, Irena; Narayanasamy, Prabagaran; Dash, Prasanta K et al. (2012) Biochemical and biologic characterization of exosomes and microvesicles as facilitators of HIV-1 infection in macrophages. J Immunol 189:744-54
Hutter-Saunders, Jessica A L; Gendelman, Howard E; Mosley, R Lee (2012) Murine motor and behavior functional evaluations for acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication. J Neuroimmune Pharmacol 7:279-88
Hutter-Saunders, Jessica A L; Mosley, Rodney Lee; Gendelman, Howard E (2011) Pathways towards an effective immunotherapy for Parkinson's disease. Expert Rev Neurother 11:1703-15
Kadiu, Irena; Nowacek, Ari; McMillan, Joellyn et al. (2011) Macrophage endocytic trafficking of antiretroviral nanoparticles. Nanomedicine (Lond) 6:975-94

Showing the most recent 10 out of 16 publications