Cocaine is a commonly used drug among HIV-infected individuals, and its use has been suggested to worsen HIV-associated neurocognitive disorders (HAND), one of the most devastating complications of AIDS. Drug-abusing HIV-1-positive individuals are known to have higher rates of HIV-encephalitis and clinical HIV dementia;the hallmarks of HAND. However, the detailed molecular mechanisms underlying the ability of cocaine to enhance these neurological effects of HIV-1 in the brain still remains to be fully understood. We propose a novel mechanism mediated by the cellular microRNA """"""""miR-125b"""""""" and the mitochondrial metabolic enzyme Proline oxidase (POX) in cocaine and HIV-1 induced neuronal damage. This is based on our preliminary data that demonstrate downregulation of miR-125b in human neurons (both primary and cell lines) upon treatment with cocaine and HIV-1 envelop glycoprotein-gp120. Concurrently, we also observed upregulation of the tumor protein 53 (p53) in cocaine and gp120 treated neuronal cells. p53 has been implicated in many cellular processes leading to neuronal damage in the HIV-1 infected central nervous system (CNS). Notably, miR-125b has been demonstrated to negatively regulate p53 in neuronal cells. Our data also illustrate upregulation of the mitochondrial metabolic enzyme Proline Oxidase (POX) in cocaine and gp120 treated human primary neurons and neuronal cell models. Since POX is induced by p53, we propose that POX is a downstream target of the miR-125b/p53 axis that may play a critical role in cocaine and HIV-1 induced neuronal damage. This is because POX generates reactive oxygen species (ROS) during the catalytic conversion of proline to pyrroline-5-carboxylate (P5C). Additionally, upregulation of POX can increase glutamate levels since P5C is a precursor of glutamate. Given that increased levels of ROS and glutamate are implicated in neuronal damage, we hypothesize that cocaine enhances HIV-1 associated neuronal damage by downregulating miR-125b and upregulating POX. We believe our proposal is highly significant since the roles of miR-125b and POX in HIV associated neuronal damage have not been previously described. Therefore, these studies may uncover a novel mechanism and identify new therapeutic targets for abrogating neuronal damage in HAND patients. Our hypothesis will be tested through two specific aims.
Aim 1 : Elucidate that cocaine and HIV-1 gp120 induced upregulation of POX induces neuronal damage.
Aim 2 : Examine that miR- 125b is a novel regulator of POX in neuronal cells.
HIV positive cocaine users show higher rates of HIV associated neurocognitive disorders (HAND). However, the mechanism by which cocaine contributes to HAND remains unclear. Therefore, the focus of this proposal is to delineate the mechanism by which cocaine accelerates HAND.
|Dash, Sabyasachi; Balasubramaniam, Muthukumar; Rana, Tanu et al. (2017) Poly (ADP-Ribose) Polymerase-1 (PARP-1) Induction by Cocaine Is Post-Transcriptionally Regulated by miR-125b. eNeuro 4:|
|Swepson, Chelsie; Ranjan, Alok; Balasubramaniam, Muthukumar et al. (2016) Cocaine Enhances HIV-1 Transcription in Macrophages by Inducing p38 MAPK Phosphorylation. Front Microbiol 7:823|
|Kaneshiro, Bliss; Edelman, Alison; Dash, Chandravanu et al. (2016) Effect of oral contraceptives and doxycycline on endometrial MMP-2 and MMP-9 activity. Contraception 93:65-9|
|Addai, Amma B; Pandhare, Jui; Paromov, Victor et al. (2015) Cocaine modulates HIV-1 integration in primary CD4+ T cells: implications in HIV-1 pathogenesis in drug-abusing patients. J Leukoc Biol 97:779-90|
|Dash, Sabyasachi; Balasubramaniam, Muthukumar; Villalta, Fernando et al. (2015) Impact of cocaine abuse on HIV pathogenesis. Front Microbiol 6:1111|
|Passaro, Ryan Colby; Pandhare, Jui; Qian, Han-Zhu et al. (2015) The Complex Interaction Between Methamphetamine Abuse and HIV-1 Pathogenesis. J Neuroimmune Pharmacol 10:477-86|
|Pandhare, Jui; Dash, Sabyasachi; Jones, Bobby et al. (2015) A Novel Role of Proline Oxidase in HIV-1 Envelope Glycoprotein-induced Neuronal Autophagy. J Biol Chem 290:25439-51|