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.
|Kim, Sarah; Hahn, Yun Kyung; Podhaizer, Elizabeth M et al. (2018) A central role for glial CCR5 in directing the neuropathological interactions of HIV-1 Tat and opiates. J Neuroinflammation 15:285|
|Wodarski, Rachel; Bagdas, Deniz; Paris, Jason J et al. (2018) Reduced intraepidermal nerve fibre density, glial activation, and sensory changes in HIV type-1 Tat-expressing female mice: involvement of Tat during early stages of HIV-associated painful sensory neuropathy. Pain Rep 3:e654|
|Gonek, Maciej; McLane, Virginia D; Stevens, David L et al. (2018) CCR5 mediates HIV-1 Tat-induced neuroinflammation and influences morphine tolerance, dependence, and reward. Brain Behav Immun 69:124-138|
|Leibrand, Crystal R; Paris, Jason J; Ghandour, M Said et al. (2017) HIV-1 Tat disrupts blood-brain barrier integrity and increases phagocytic perivascular macrophages and microglia in the dorsal striatum of transgenic mice. Neurosci Lett 640:136-143|
|Hauser, Kurt F; Knapp, Pamela E (2017) Opiate Drugs with Abuse Liability Hijack the Endogenous Opioid System to Disrupt Neuronal and Glial Maturation in the Central Nervous System. Front Pediatr 5:294|
|Patel, Sulay; Leibrand, Crystal R; Palasuberniam, Preetha et al. (2017) Effects of HIV-1 Tat and Methamphetamine on Blood-Brain Barrier Integrity and Function In Vitro. Antimicrob Agents Chemother 61:|
|Schier, Christina J; Marks, William D; Paris, Jason J et al. (2017) Selective Vulnerability of Striatal D2 versus D1 Dopamine Receptor-Expressing Medium Spiny Neurons in HIV-1 Tat Transgenic Male Mice. J Neurosci 37:5758-5769|
|Dickens, Alex M; Yoo, Seung Wan; Chin, Alfred C et al. (2017) Chronic low-level expression of HIV-1 Tat promotes a neurodegenerative phenotype with aging. Sci Rep 7:7748|
|Balinang, Joyce M; Masvekar, Ruturaj R; Hauser, Kurt F et al. (2017) Productive infection of human neural progenitor cells by R5 tropic HIV-1: opiate co-exposure heightens infectivity and functional vulnerability. AIDS 31:753-764|
|Marks, William D; Paris, Jason J; Schier, Christina J et al. (2016) HIV-1 Tat causes cognitive deficits and selective loss of parvalbumin, somatostatin, and neuronal nitric oxide synthase expressing hippocampal CA1 interneuron subpopulations. J Neurovirol 22:747-762|
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