Effects of HIV-1 Tat protein and methamphetamine on VMAT2-mediated dopamine transmission in the context of neuroHIV and drug abuse

HIV-1 Tat 蛋白和甲基苯丙胺对神经 HIV 和药物滥用背景下 VMAT2 介导的多巴胺传递的影响

基本信息

项目摘要

PROJECT SUMMARY More than 38 million people are living with Human Immunodeficiency Virus (HIV) infection worldwide which continues to be a global public health problem. Despite the widespread use of efficacious combination of antiretroviral therapy (cART), up to 70% of HIV-positive individuals suffer from cognitive and behavioral deficits collectively known as HIV associated neurocognitive disorders (HAND). Although acute viral replication has been well controlled with cART in the early stage of HIV infection, long-term HIV-1 viral protein exposure within the CNS causes dopaminergic deficits and neurocognitive impairments despite the advent of cART. Substance abuse such as methamphetamine (METH) have been shown to increase the incidence of HAND and exacerbate its severity. Among the viral proteins, HIV-1 transactivator of transcription (Tat) protein plays a significant role in viral replication in the early stage of HIV infection and the pathophysiological effects on development of HAND. Dopamine (DA) transporter (DAT) transports the extracellular dopamine (DA) into cytosolic space of the synaptic terminals, whereas the vesicular monoamine transporter2 (VMAT2) transports the cytosolic DA into synaptic vesicles, whereby both DA transporter and VMAT2 are critical for normal DA homeostasis. Our published studies have demonstrated that Tat protein increases extracellular DA concentration by directly inhibiting DAT, however, the cellular mechanisms underlying Tat-induced inhibition of VMAT2-mediated DA release/uptake remains unexplored. We hypothesize that HIV-1 Tat, acting via the unique binding sites, perturbs the VMAT2 regulatory network that normally sustains concentrative DA transport and potentiates METH’s effect on VMAT2 function, resulting in DA-linked neuropsychiatric dysfunction prominently featured in HAND. Studying single Tat protein allow us to identify targets for Tat binding and develop therapeutic approaches to prevent Tat-mediated neurological damages. The purpose of the proposed investigation is to understand the molecular mechanisms of dysregulation of VMAT2-mediated DA transmission induced by HIV-1 Tat and METH and explore the potential of novel compounds for the prevention of HAND. The specific aims to be pursued in the proposed investigation are: (1) through computational modeling and experimental validation, identify the recognition binding pockets on human VMAT2 for Tat, METH, or novel VMAT2 inhibitors and explore the potential interactions of the inhibitors with Tat and METH, (2) accelerate the pathophysiological roles of VMAT2 in Tat- and METH-dysregulated DA system, and (3) perform proof-of-concept studies using pharmacological and genetic approaches as biological probes to establish their potential for therapeutic application in HAND in concurrent METH users.
项目总结

项目成果

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CHANG-GUO ZHAN其他文献

CHANG-GUO ZHAN的其他文献

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{{ truncateString('CHANG-GUO ZHAN', 18)}}的其他基金

Long-acting aldicarb hydrolase as a medical countermeasure for aldicarb poisoning
长效涕灭威水解酶作为涕灭威中毒的医学对策
  • 批准号:
    10724752
  • 财政年份:
    2023
  • 资助金额:
    $ 65.46万
  • 项目类别:
Ghrelin Deacylase as a Treatment for Opioid Polysubstance Abuse
生长素释放肽脱酰酶治疗阿片类多物质滥用
  • 批准号:
    10510245
  • 财政年份:
    2022
  • 资助金额:
    $ 65.46万
  • 项目类别:
Development of a Long-acting Enzyme Therapy for Treatment of Cocaine Abuse
开发治疗可卡因滥用的长效酶疗法
  • 批准号:
    10405101
  • 财政年份:
    2020
  • 资助金额:
    $ 65.46万
  • 项目类别:
Development of a Long-acting Enzyme Therapy for Treatment of Cocaine Abuse
开发治疗可卡因滥用的长效酶疗法
  • 批准号:
    10231091
  • 财政年份:
    2020
  • 资助金额:
    $ 65.46万
  • 项目类别:
Computational Core
计算核心
  • 批准号:
    10569666
  • 财政年份:
    2020
  • 资助金额:
    $ 65.46万
  • 项目类别:
Computational Core
计算核心
  • 批准号:
    10112943
  • 财政年份:
    2020
  • 资助金额:
    $ 65.46万
  • 项目类别:
Computational Core
计算核心
  • 批准号:
    10333388
  • 财政年份:
    2020
  • 资助金额:
    $ 65.46万
  • 项目类别:
Development of Long-acting Cocaine Hydrolase as a Treatment for Cocaine Abuse
开发长效可卡因水解酶来治疗可卡因滥用
  • 批准号:
    9754089
  • 财政年份:
    2015
  • 资助金额:
    $ 65.46万
  • 项目类别:
Development of Long-acting Cocaine Hydrolase as a Treatment for Cocaine Abuse
开发长效可卡因水解酶来治疗可卡因滥用
  • 批准号:
    9139953
  • 财政年份:
    2015
  • 资助金额:
    $ 65.46万
  • 项目类别:
Long-lasting cocaine-metabolizing enzyme for cocaine addiction treatment
用于可卡因成瘾治疗的长效可卡因代谢酶
  • 批准号:
    8636423
  • 财政年份:
    2013
  • 资助金额:
    $ 65.46万
  • 项目类别:

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