This is a revised Exploratory/Developmental R21 application (1 R21 DA019836-01). The main goal of our research is to explore the effects of opiates, such as morphine, on the HIV-1-induced inflammation and cytotoxicity that takes place in the brain. We will be using a newly developed HIV-1 transgenic rat as a model system and recently developed """"""""proteomic and genomic"""""""" techniques, respectively, such as antibody microarray and DMA microarray technology, along with other cutting edge methodologies including double labeling fluorescence immunocytochemistry, and Taq-Man probe real time RT-PCR. It is well-recognized that various cytokins (such as TNF-alpha and IL-1beta) and chemokines (such as MIP-1) are induced to mediate HIV-1-induced neuroinflammation and that neurons in AIDS patients die via apoptosis and activation of the effector, such as caspase-3. This apoptosis then leads to neurodegeneration. Opiates, such as morphine, have been reported to alter the serum levels of several cytokines, including TNF-alpha, which is secreted in response to an immune challenge; and potentiate Tat- induced apoptosis of neuronal cells and astrocytes along with enhanced activation of caspase-3. We, therefore, hypothesize that exposure to morphine augments the effects of HIV-1 in deregulating the expression of cytokines and chemokines, leading to accelerated inflammation and apoptosis in the brain. The following specific aims are designed to test this hypothesis: 1) To determine morphine's effects on HIV- 1-induced inflammation by determining cytokine/chemokine expression using oligo DMA micorarray and antibody microarray; and 2) To assess morphine's effects on HIV-1-induced cytotoxicity in vivo by measuring changes in neurons (NeuN-labeled cells), astrocytes (glial fibrillary acidic protein-labeled cells), and synapses (using synaptophsin and SNAP-25 to identify synapses) in combination with phosphorylated caspase-3 immunocytochemistry and the TUNEL assay. If successful, this HIV-1 transgenic rat model and the data generated from its use may shed light on molecular and cellular mechanism(s) underlying the neurotoxicity and neuropathogenesis in HIV patients with or without morphine usage, and may lead investigators to develop research projects with a new direction or new therapeutic applications. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21DA019836-02
Application #
7230049
Study Section
Special Emphasis Panel (ZRG1-AARR-A (05))
Program Officer
Purohit, Vishnudutt
Project Start
2006-05-01
Project End
2008-04-30
Budget Start
2007-05-01
Budget End
2008-04-30
Support Year
2
Fiscal Year
2007
Total Cost
$191,381
Indirect Cost
Name
Seton Hall University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
079324315
City
South Orange
State
NJ
Country
United States
Zip Code
07079
Byrne, Linda Staikos; Peng, Jinsong; Sarkar, Sraboni et al. (2012) Interleukin-1 beta-induced up-regulation of opioid receptors in the untreated and morphine-desensitized U87 MG human astrocytoma cells. J Neuroinflammation 9:252
Peng, Jinsong; Sarkar, Sraboni; Chang, Sulie L (2012) Opioid receptor expression in human brain and peripheral tissues using absolute quantitative real-time RT-PCR. Drug Alcohol Depend 124:223-8
Langsdorf, Erik F; Mao, Xin; Chang, Sulie L (2011) A role for reactive oxygen species in endotoxin-induced elevation of MOR expression in the nervous and immune systems. J Neuroimmunol 236:57-64
Peng, Jinsong; Vigorito, Michael; Liu, Xiangqian et al. (2010) The HIV-1 transgenic rat as a model for HIV-1 infected individuals on HAART. J Neuroimmunol 218:94-101
Liu, Xiangqian; Chang, Linda; Vigorito, Michael et al. (2009) Methamphetamine-induced behavioral sensitization is enhanced in the HIV-1 transgenic rat. J Neuroimmune Pharmacol 4:309-16
Staikos, Linda; Malellari, Lorenc; Chang, Sulie L (2008) Lipopolysaccharide-induced pro-inflammatory cytokines in the brain of rats in the morphine-tolerant state. J Neuroimmune Pharmacol 3:236-40
Vigorito, Michael; LaShomb, Abigail L; Chang, Sulie L (2007) Spatial learning and memory in HIV-1 transgenic rats. J Neuroimmune Pharmacol 2:319-28
Chang, Sulie L; Beltran, Jose A; Swarup, Shilpa (2007) Expression of the mu opioid receptor in the human immunodeficiency virus type 1 transgenic rat model. J Virol 81:8406-11
Persidsky, Yuri; Fox, Howard (2007) Battle of animal models. J Neuroimmune Pharmacol 2:171-7