A K02 independent Scientist Award will enable the candidate to obtain maximally protected time at Virginia Commonwealth University (VCU) to pursue NIDA funded research on substance abuse-HIV-1 comorbidity, acquire advanced cross-disciplinary expertise, and to mentor student and faculty scientists in this area. Drug abuse and HIV-1 are interlinked epidemics with horrific consequences. To address this problem, the candidate directs grants R01 DA018633, "Mechanisms of opiate drug-HIV-induced neurodegeneration" and R01 DA033200 "Regulation of HIV and opiate-directed synaptodendritic injury/death in striatum", and is a multi-Pl on R01 DA034231 "Glial origins of HIV and opiate-driven synaptodendritic injury", and is a co-l on other grants and consultant on numerous other projects. The applicant has published seminal studies demonstrating: that opioids can directly affect CNS maturation;the cellular basis of opioid receptor and function in astrocytes and oligodendrocytes;and that opioids intrinsically exacerbate the pathogenesis of neuroAIDS-identifying both intra- and intercellular pathologic mechanisms in neurons and multiple glial types. The applicant has established worldwide collaborations that continue to optimize approaches to opioid abuse-HIV-1 comorbidity, has mentored highly successful pre- and postdoctoral, and basic and clinical faculty;including training in the responsible conduct of research (RCR), has co-directed a NIDA training grant, and organized local and international conferences promoting substance abuse research. A K02 award will enable the candidate to: (1) pursue the goals of current grants, while developing cutting-edge approaches to substance abuse (e.g., whole-cell patch-clamp electrophysiology) to assess the trigger events underlying opiate and HIV interactive synaptodendritic injury) and better models of substance abuse (self-administration). (2) To merge basic and clinical approaches through translational research using engineered HIV proviral vectors as a novel source non-infectious HIV/"virotoxins" for studying electrophysiological effects in bystander neurons and to adopt CRISPRs (clustered regularly interspaced short palindromic repeats), a genome editing strategy, with the goal of completely eliminating or adding receptor genes (e.g., OPRM1). The candidate will continue to mentor students/early career scientists (including under-represented individuals and with an emphasis on RCR). He was recruited to VCU by the Dept. of Pharmacology and Toxicology to pursue these goals and receives tremendous support for this endeavor.
Opioid (heroin) abuse and HIV/AIDS are interrelated epidemics. Not only does drug abuse spread HIV, but the candidate also discovered that opioids intrinsically promote the neurodegenerative effects of HIV in the brain. The candidate respectfully requests this award to devote significant time to pursue cutting-edge research into the fundamental mechanisms underlying opioid drug abuse-HIV interactions to identify new therapies for opioid abuse and neuroAIDS.
|Fitting, Sylvia; Knapp, Pamela E; Zou, Shiping et al. (2014) Interactive HIV-1 Tat and morphine-induced synaptodendritic injury is triggered through focal disruptions in Na? influx, mitochondrial instability, and Ca²? overload. J Neurosci 34:12850-64|
|El-Hage, Nazira; Rodriguez, Myosotys; Podhaizer, Elizabeth M et al. (2014) Ibudilast (AV411), and its AV1013 analog, reduce HIV-1 replication and neuronal death induced by HIV-1 and morphine. AIDS 28:1409-19|
|Masvekar, Ruturaj R; El-Hage, Nazira; Hauser, Kurt F et al. (2014) Morphine enhances HIV-1SF162-mediated neuron death and delays recovery of injured neurites. PLoS One 9:e100196|
|Sorrell, Mary E; Hauser, Kurt F (2014) Ligand-gated purinergic receptors regulate HIV-1 Tat and morphine related neurotoxicity in primary mouse striatal neuron-glia co-cultures. J Neuroimmune Pharmacol 9:233-44|
|Dever, Seth M; Costin, Blair N; Xu, Ruqiang et al. (2014) Differential expression of the alternatively spliced OPRM1 isoform ?-opioid receptor-1K in HIV-infected individuals. AIDS 28:19-30|
|Ngwainmbi, Joy; De, Dipanjana D; Smith, Tricia H et al. (2014) Effects of HIV-1 Tat on enteric neuropathogenesis. J Neurosci 34:14243-51|
|Hauser, Kurt F; Knapp, Pamela E (2014) Interactions of HIV and drugs of abuse: the importance of glia, neural progenitors, and host genetic factors. Int Rev Neurobiol 118:231-313|
|El-Hage, Nazira; Dever, Seth M; Podhaizer, Elizabeth M et al. (2013) A novel bivalent HIV-1 entry inhibitor reveals fundamental differences in CCR5-*-opioid receptor interactions between human astroglia and microglia. AIDS 27:2181-90|
|Fitting, Sylvia; Ignatowska-Jankowska, Bogna M; Bull, Cecilia et al. (2013) Synaptic dysfunction in the hippocampus accompanies learning and memory deficits in human immunodeficiency virus type-1 Tat transgenic mice. Biol Psychiatry 73:443-53|
|El-Hage, Nazira; Podhaizer, Elizabeth M; Sturgill, Jamie et al. (2011) Toll-like receptor expression and activation in astroglia: differential regulation by HIV-1 Tat, gp120, and morphine. Immunol Invest 40:498-522|
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