Grants and Contracts Details
Description
The opioid system plays a fundamental role in the pathogenesis of AIDS. Brain r,,}gions expressing a high
number/density of opioid receptors. such as the striatum and hippocampus, displelY increased viral load and
are preferentially decimated by HIV infection. The progression to AIDS dementia in HIV-positive individuals
may also be markedly accelerated in opiate drug abusers. Although the virus itself propagates in microglia
and astroglia, HIV-1 proteins such as gp120 and Tat. are subsequently released and cause degeneration in
neighboring neurons. "Opiates" (substances derived from the opium poppy, such as heroin) or analogues (e.
go, OxyContin) are popular drugs of abuse. Although many aspects of HIV are CGlused indirectly by infected
macrophagesJmicroglial cells, direct toxic effects of the viral proteins themselves ~n be seen in isolated
neurons. This direct neurotoxicity is exacerbated by mu opiate drugs. This propc,sal focuses on the
interactions between mu opioids and HIV-1 proteins that result in direct synergistit:~ neurotoxicity. Morphine
synergistically increases Tat neurotoxicity via a pathway that is mediated in part by caspase-3. Our
hypothesis is that opiates exacerbate neurodegenerative effects of HIV-1 by disrupting cellular homeostasis
and increasing the probability of pro-apoptotic intracellular events. Disruptions in premitochondrial pathways
involving PI3K. Akt. PTEN, calcium, calcineurin, and GSK3beta will be examined for effects on both caspase-
3 dependent and independent (endonuclease-G) cell death using pharmacologiccll, transfection (silencing!
overexpression vectors) and genetic strategies [caspase-3(-/-) and PTEN(+!-) mice]. Complementary in vivo!
in vitro approaches will identify the mechanisms by which mu opiates affect the survival of gp120lTatcompromised
striatal neurons. Aim 1 will explore the mechanisms by which opiate drugs exacerbate gp1201
Tat-induced neuronal death in vitro. Aim 2 will identify the effects of opiates on gp120lTat-induced
neurotoxicity in vivo using conditional Tat and gp120 expressing transgenic mice, and caspase-3 knockout
and PTEN-deficient mice injected intrastriatally with TaUgp120. Our long-term goal is to define the
mechanisms by which opiate drug abuse contributes to neurodegeneration accompanying HIVE in the CNS,
and to identify the undenying signaling pathways that could be targeted for therapeutic intervention
Status | Finished |
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Effective start/end date | 9/30/05 → 6/30/07 |
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