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Education

Ph.D.  Biochemistry, Fukui Medical University, Japan, 1998
M.D.   Zhejiang University, China, 1982

Postdoctoral Fellowship
Neuropharmacology, University of Kentucky, 2006

Research Interests

The Zhu lab is interested in the role of HIV-1 viral proteins in NeuroAIDS. About one-half of HIV-1-positive individuals suffer from HIV-associated neurocognitive disorders (HAND), which dramatically affects memory, learning, decision-making, planning and overall quality of life. Drugs of abuse, such as cocaine, have been shown to exacerbate the severity of HAND. HAND is associated with HIV-1 viral proteins, which are present in the brain of HIV-1-infected patients. For a long time, the idea of the HIV virus crossing the blood-brain barrier was not even considered, but it’s now clear that HIV-1 viral proteins are released in the brain where they disrupt normal brain functions. HIV-1 transactivator of transcription (Tat) protein, an HIV regulatory protein, is thought to inhibit neuronal communication by acting directly on the human dopamine transporter (hDAT) and norepinephrine transporter (hNET), membrane proteins in the brain responsible for pumping the dopamine/norepinephrine back into the cytosol and terminating the monoamine signaling during neurotransmission. The Zhu lab uses cutting edge computational modeling, pharmacological, genetic, and behavioral techniques to identify the mechanism by which Tat perturbs the DAT and NET regulatory network that normally sustains concentrative the neurotransmitters and potentiates cocaine’s effect on DAT and NET, resulting in dopamine/norepinephrine-linked neuropsychiatric dysfunction prominently featured in HAND

Our currently funded projects are generally based around mechanisms of Tat-DAT/NET interaction and Tat-induced neurocognition deficits and potentiation of cocaine reward in HIV-1 Tat transgenic mouse model. Our primary work investigates whether Tat-induced inhibition of DAT/NET is mediated by binding to allosteric binding site(s) on DAT/NET, not by interacting with the DA uptake site. Accordingly, attenuating Tat binding to DAT/NET would be expected to have minimal influence on physiological DA transport. A major goal is to identify and understand the recognition binding sites on DAT/NET for Tat and associated transporter conformational transitions. New projects are extending these findings to perform proof of concept studies using novel allosteric modulators to establish their potential for therapeutic application in HAND.

The Zhu Lab is also interested in exploring new theories about why some people may be more predisposed to addiction than others, and whether preemptive treatments could stop people from becoming addicted in the first place. Tobacco use is the number one preventable cause of death in the United States. This project is to study how environmental factors, through modulation of small RNAs and intracellular signaling, reduce nicotine’s rewarding effects. This research project will provide insights into impact of a unique microRNA regulation in drug rewarding and has a high impact in the field of drug abuse research.

Research Interests

• HIV-1 Tat protein-mediated regulation of human dopamine transporter
• Individual differences in the vulnerability to nicotine dependence

Research Expertise

• Neuropsychopharmacology
• Drug addiction
• NeuroAIDS

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Publications

Zhu J, Zhan CG, and Ananthan S. The role of human dopamine transporter in NeuroAIDS. Pharmacology & Therapeutics 183:78-89. 2018 PMCID: PMC5817011

Sun WL, Quizon PM, Yuan Y, Zhang W, Ananthan S, Zhan CG, and Zhu J. Allosteric modulatory effects of SRI-20041 and SRI-30827 on cocaine and HIV-1 Tat protein binding to human dopamine transporter. Nature Scientific Reports 7(1):3694. 2017 PMCID: PMC5473888

Quizon PM, Sun WL, Yuan Y, Midde NM, Zhan CG, and Zhu J. Molecular mechanism: the human dopamine transporter histidine 547 regulates basal and HIV-1 Tat protein-inhibited dopamine transport. 2016 Nature Scientific Reports 6:39048. 2016 PMCID: PMC515529

Yuan Y, Huang X, Zhu J, and Zhan C. G. Computational modeling of human dopamine transporter structures, mechanism and its interaction with HIV-1 transactivator of transcription. Future medicinal chemistry 8(17) Oct 14. 2016 PMID: 27739323

Yuan Y, Quizon PM, Sun WL, Yao JZ, Zhu J, and Zhan CG. Role of Histidine 547 of Human Dopamine Transporter in Molecular Interaction with HIV-1 Tat and Dopamine Uptake. Nature Scientific Reports 6:27314. 2016 PMID: 27250920

Sun WL, Quizon PM, Zhu J. Molecular Mechanism: ERK Signaling, Drug Addiction, and behavioral Effects. Prog Mol Biol Transl Sci 137:1-40. 2016 PMCID: PMC5330621 (as a corresponding author). Impact factor in 2016: 2.984

Zhu J, Yuan Y, Midde NM, Gomez AM, Sun WL, Quizon PM, Zhan CG. HIV-1 transgenic rats display an increase in [3H]dopamine uptake in the prefrontal cortex and striatum. Journal of NeuroVirology 22(3):282-292. 2015 PMCID: PMC5330645

Gomez AM, Altomare D, Sun WL, Midde NM, Ji H, Shtutman M, Turner JR, Creek KE, Zhu J. Prefrontal microRNA-221 mediates environmental enrichment-induced increase of locomotor sensitivity to nicotine. The International Journal of Neuropsychopharmacology 19(1). 2015 PMCID: PMC4772274

Zhu J, Midde NM, Gomez AM, Sun WL, Harrod SB. Intra-ventral tegmental area HIV-1 Tat1-86 attenuates nicotine-mediated locomotor sensitization and alters mesocorticolimbic ERK and CREB signaling in rats. Frontier in Microbiology 6:540. 2015 PMCID: PMC4473058

Yuan Y, Huang X, Midde NM, Quizon PM, Sun WL, Zhu J, Zhan CG. Molecular mechanism of HIV-1 Tat interacting with human dopamine transporter. ACS Chemical Neuroscience 6(4):658-665. 2015 PMCID: PMC4400243

Midde NM, Yuan Y, Quizon PM, Sun WL, Huang X, Zhan CG, Zhu J. Mutations at Tyrosine 88, Lysine 92 and Tyrosine 470 of Human Dopamine Transporter Result in an Attenuation of HIV-1 Tat-Induced Inhibition of Dopamine Transport. J Neuroimmune Pharmacol 10(1):122-135. 2015 PMCID: PMC4388869

Gomez AM, Sun WL, Midde NM, Harrod SB, Zhu J. Effects of environmental enrichment on ERK1/2 phosphorylation in the rat prefrontal cortex following nicotine-induced sensitization or nicotine self-administration. European Journal of Neuroscience 41(1):109-19. 2015 PMCID: PMC4285565

Midde NM, Huang X, Gomez AM, Booze RM, Zhan CG, Zhu J. Mutation of Tyrosine 470 of human dopamine transporter is critical for HIV-1 Tat-induced inhibition of dopamine transport and transporter conformational transitions. J Neuroimmune Pharmacol 8:975-987. 2013 PMCID: PMC3740080

Zhu J, Bardo MT, Dwoskin LP. Distinct effects of enriched environment on dopamine clearance in nucleus accumbens shell and core following systemic nicotine administration. Synapse 67:57-67. 2013 PMCID: PMC3786350

Gomez AM, Midde NM, Mactutus CF, Booze RM, Zhu J. Environmental Enrichment Alters Nicotine-Mediated Locomotor Sensitization and Phosphorylation of DARPP-32 and CREB in Rat Prefrontal Cortex. PLos One 7(8):e44149. 2012 PMCID: PMC3432100

Midde NM, Gomez AM, Zhu J. HIV-1 Tat Protein Decreases Dopamine Transporter Cell Surface Expression and Vesicular Monoamine Transporter-2 Function in Rat Striatal Synaptosomes. J Neuroimmune Pharmacol 7(3):629-639. 2012 PMCID: PMC3688268        

Zhu J, Ananthan S, Mactutus CF and Booze RM. Recombinant human immunodeficiency virus-1 transactivator of transcription (1-86) allosterically modulates dopamine transporter activity. Synapse 65:1251-1254. 2011 PMCID: PMC3676522

Midde NM, Gomez AM, Harrod SB and Zhu J. Genetically expressed HIV-1 viral proteins attenuate nicotine-induced behavioral sensitization and alter mesocorticolimbic ERK and CREB signaling in rats. Pharmacology Biochemistry and Behavior 98:587-597. 2011 PMCID: PMC3091851

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