Grants and Contracts Details
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
|Effective start/end date||9/30/05 → 6/30/07|
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