Single cell brain transcriptome changes during chronic HIV infection and opiate use in conventional mice

传统小鼠慢性艾滋病毒感染和阿片类药物使用期间单细胞脑转录组的变化

基本信息

  • 批准号:
    10594562
  • 负责人:
  • 金额:
    $ 250.66万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-05-15 至 2026-01-31
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY This application is submitted in response to RFA-D-21-019: Single Cell Opioid Responses in the Context of HIV (SCORCH) Program Expansion: CNS Data Generation for Chronic Opioid, Methamphetamine, and/or Cocaine Exposures. Human immunodeficiency virus (HIV) can infect nonneuronal cells in the brain, particularly microglia, with these cells acting as a reservoir of latent infection. HIV infection has deletions effects on the function of nonneuronal and neuronal cells, including those cells located in brain sites relevant to cognition, emotion and motivation. The same brain sites impacted by HIV are known to regulate the actions of opioids and other classes of addictive drugs, and opioid use disorder (OUD) is more prevalent in HIV-infected individuals than the general population. Moreover, HIV infection and OUD reciprocally interact, with each condition potentially exacerbating the severity of the other. Mice infected with EcoHIV, a modified HIV strain that targets CD4+ T cells, macrophages and microglia, recapitulates the major pathobiological features of chronic HIV infection in individuals on antiretroviral therapy (ART). Here, we will leverage state-of-the-art single cell sequencing (scSeq), molecular, cellular and behavioral approaches to define cell type-specific interactions between HIV and opioids in the brains of EcoHIV-infected mice. In Specific Aim I, we optimize the intravenous (IV) heroin self-administration procedure, already well-established in our laboratories, for use in EcoHIV- infected mice. We will then examine the effects of EcoHIV infection on the expression of opioid addiction-relevant behaviors. Conversely, we will examine the effects of heroin consumption on the expression of cognitive abnormalities in EcoHIV-infected mice relevant to HIV-associated neurocognitive impairment (HIV-NCI) in humans. Finally, will examine the effects of ART on the expression of addiction- and HIV-NCI-relevant behavioral abnormalities in EcoHIV-infected mice. In Specific Aim II, we will perform scSeq on brain regions relevant to opioid addiction and HIV-NCI, collected from EcoHIV mice with our without a history of intravenous opioid self- administration behavior. We will investigate the effects of ART on scSeq patterns in these mice. The scSeq data will be mined to identify cells in the brain infected by EcoHIV, and determine which cells show the most robust transcriptional responses to EcoHIV in opioid-naïve and opioid-experienced mice. In situ hybridization and immunohistochemistry will be used to validate key findings and prioritize candidate genes for further investigation. In Specific Aim III, we will use in vivo CRISPR-Cas9 to target prioritized genes identified in Aim II in a cell type- and brain region-specific manner. The impact of CRISPR cleavage of prioritized genes on the expression of addiction- and HIV-NCI-relevant behavioral abnormalities in EcoHIV-infected mice will be examined. This innovative program of research may yield fundamental new insights into disease-relevant interactions between HIV infection and opioid drugs.
项目总结

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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Paul J. Kenny其他文献

The single-cell opioid responses in the context of HIV (SCORCH) consortium
人类免疫缺陷病毒(HIV)背景下的单细胞阿片类药物反应(SCORCH)联盟
  • DOI:
    10.1038/s41380-024-02620-7
  • 发表时间:
    2024-06-15
  • 期刊:
  • 影响因子:
    10.100
  • 作者:
    Seth A. Ament;Rianne R. Campbell;Mary Kay Lobo;Joseph P. Receveur;Kriti Agrawal;Alejandra Borjabad;Siddappa N. Byrareddy;Linda Chang;Declan Clarke;Prashant Emani;Dana Gabuzda;Kyle J. Gaulton;Michelle Giglio;Federico M. Giorgi;Busra Gok;Chittibabu Guda;Eran Hadas;Brian R. Herb;Wen Hu;Anita Huttner;Mohammad R. Ishmam;Michelle M. Jacobs;Jennifer Kelschenbach;Dong-Wook Kim;Cheyu Lee;Shuhui Liu;Xiaokun Liu;Bertha K. Madras;Anup A. Mahurkar;Deborah C. Mash;Eran A. Mukamel;Meng Niu;Richard M. O’Connor;Chelsea M. Pagan;Alina P. S. Pang;Piya Pillai;Vez Repunte-Canonigo;W. Brad Ruzicka;Jay Stanley;Timothy Tickle;Shang-Yi A. Tsai;Allen Wang;Lauren Wills;Alyssa M. Wilson;Susan N. Wright;Siwei Xu;Junchen Yang;Maryam Zand;Le Zhang;Jing Zhang;Schahram Akbarian;Shilpa Buch;Christine S. Cheng;Michael J. Corley;Howard S. Fox;Mark Gerstein;Suryaram Gummuluru;Myriam Heiman;Ya-Chi Ho;Manolis Kellis;Paul J. Kenny;Yuval Kluger;Teresa A. Milner;David J. Moore;Susan Morgello;Lishomwa C. Ndhlovu;Tariq M. Rana;Pietro Paolo Sanna;John S. Satterlee;Nenad Sestan;Stephen A. Spector;Serena Spudich;Hagen U. Tilgner;David J. Volsky;Owen R. White;Dionne W. Williams;Hongkui Zeng
  • 通讯作者:
    Hongkui Zeng
Binge drinking and brain stress systems
酗酒和大脑压力系统
  • DOI:
    10.1038/520168a
  • 发表时间:
    2015-04-08
  • 期刊:
  • 影响因子:
    48.500
  • 作者:
    Richard M. O'Connor;Paul J. Kenny
  • 通讯作者:
    Paul J. Kenny
Binge drinking and brain stress systems
酗酒和大脑压力系统
  • DOI:
    10.1038/520168a
  • 发表时间:
    2015-04-08
  • 期刊:
  • 影响因子:
    48.500
  • 作者:
    Richard M. O'Connor;Paul J. Kenny
  • 通讯作者:
    Paul J. Kenny
Chronic stress drives depression by disrupting cellular housekeeping
慢性应激通过破坏细胞的内环境稳定来引发抑郁症。
  • DOI:
    10.1038/d41586-025-00910-w
  • 发表时间:
    2025-04-09
  • 期刊:
  • 影响因子:
    48.500
  • 作者:
    Alberto Corona;Paul J. Kenny
  • 通讯作者:
    Paul J. Kenny

Paul J. Kenny的其他文献

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{{ truncateString('Paul J. Kenny', 18)}}的其他基金

Single cell transcriptomic and epigenomic changes during chronic HIV infection and cocaine self-administration
慢性艾滋病毒感染和可卡因自我给药期间的单细胞转录组和表观基因组变化
  • 批准号:
    10629335
  • 财政年份:
    2022
  • 资助金额:
    $ 250.66万
  • 项目类别:
Single cell transcriptomic and epigenomic changes during chronic HIV infection and cocaine self-administration
慢性艾滋病毒感染和可卡因自我给药期间的单细胞转录组和表观基因组变化
  • 批准号:
    10454708
  • 财政年份:
    2022
  • 资助金额:
    $ 250.66万
  • 项目类别:
Single cell brain transcriptome changes during chronic HIV infection and opiate use in conventional mice
传统小鼠慢性艾滋病毒感染和阿片类药物使用期间单细胞脑转录组的变化
  • 批准号:
    10405624
  • 财政年份:
    2021
  • 资助金额:
    $ 250.66万
  • 项目类别:
Training Program in Substance Use Disorders
药物滥用障碍培训计划
  • 批准号:
    10623170
  • 财政年份:
    2021
  • 资助金额:
    $ 250.66万
  • 项目类别:
Training Program in Substance Use Disorders
药物滥用障碍培训计划
  • 批准号:
    10206956
  • 财政年份:
    2021
  • 资助金额:
    $ 250.66万
  • 项目类别:
Training Program in Substance Use Disorders
药物滥用障碍培训计划
  • 批准号:
    10383775
  • 财政年份:
    2021
  • 资助金额:
    $ 250.66万
  • 项目类别:
Single cell brain transcriptome changes during chronic HIV infection and opiate use in conventional mice
传统小鼠慢性艾滋病毒感染和阿片类药物使用期间单细胞脑转录组的变化
  • 批准号:
    10220584
  • 财政年份:
    2021
  • 资助金额:
    $ 250.66万
  • 项目类别:
Role for Tas2Rs in opioid addiction
Tas2Rs 在阿片类药物成瘾中的作用
  • 批准号:
    10177030
  • 财政年份:
    2020
  • 资助金额:
    $ 250.66万
  • 项目类别:
Role for Circular RNAs in Compulsive Cocaine Intake
环状 RNA 在强迫性可卡因摄入中的作用
  • 批准号:
    10533296
  • 财政年份:
    2019
  • 资助金额:
    $ 250.66万
  • 项目类别:
Role for Circular RNAs in Compulsive Cocaine Intake
环状 RNA 在强迫性可卡因摄入中的作用
  • 批准号:
    10306369
  • 财政年份:
    2019
  • 资助金额:
    $ 250.66万
  • 项目类别:

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戒酒期间运动诱导的岛叶皮质微电路调节
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吸毒大学生急性数字媒体戒断的神经生物学影响
  • 批准号:
    10677380
  • 财政年份:
    2023
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    $ 250.66万
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Single-cell whole brain imaging of nicotine intoxication, dependence, and abstinence
尼古丁中毒、依赖和戒断的单细胞全脑成像
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了解酒精使用障碍的恢复:两个自愿临时戒酒期的纵向观察
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  • 财政年份:
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    $ 250.66万
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    2022
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    $ 250.66万
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