Single nucleus gene expression in moderate and compulsive drug self-administration in a rodent model of HIV
HIV啮齿动物模型中度和强迫性自我给药的单核基因表达
基本信息
- 批准号:10454706
- 负责人:
- 金额:$ 133.83万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-03-15 至 2026-11-30
- 项目状态:未结题
- 来源:
- 关键词:AddressAdoptedAlzheimer&aposs DiseaseAnimal ModelAstrocytesAutomobile DrivingBehaviorBehavioral ParadigmBindingBrain regionCell NucleusCellsChronicClinicalComputing MethodologiesContractsDSM-IVDSM-VDataData Coordinating CenterDevelopmentDiseaseDisease ProgressionDrug AddictionDrug usageFreezingGene ExpressionGenesGenomicsGoalsHIVHIV InfectionsHIV-1HeadHumanImpairmentIntakeIntravenousLeadLymphocyteMalignant NeoplasmsMethamphetamineMethamphetamine use disorderMethodsMicrogliaModelingMolecularNerve DegenerationNeuraxisNeuronsNeuropathogenesisNeuropsychologyNeurosciencesPathogenicityPathway AnalysisPatientsPatternPersonsPharmaceutical PreparationsProteinsRat-1RattusRecording of previous eventsRegulationRegulator GenesResearch PersonnelResolutionResourcesRodent ModelSamplingSelf AdministrationSmall Nuclear RNASubstance Use DisorderSynapsesSystems BiologyTestingTherapeuticTissuesTranscriptTransgenesTransgenic OrganismsUrsidae FamilyValidationViruscell typecomorbiditydrug mechanismexperiencegene networkgene regulatory networkgenetic signaturegenome-widehigh throughput analysisimprovedmacrophagemethamphetamine abusemethamphetamine effectmethamphetamine usenerve injuryneuroAIDSneuroinflammationnew therapeutic targetnovelnovel therapeuticspublic health relevancereconstructionrelating to nervous systemsingle cell analysisstimulant abusetargeted treatmenttherapeutic targettranscriptome sequencingtranscriptomicsvalidation studies
项目摘要
Summary
The abuse of stimulants such as methamphetamine (METH) exacerbates the deleterious effects of HIV
infection. Here, we will carry out single nucleus RNA-Seq with the goal of identifying cell types and cell states
that are pivotal in the effects of HIV and chronic methamphetamine (METH) self-administration on key brain
regions relevant to the effects of persistent HIV infection and METH use disorder in HIV transgenic (Tg) rats,
which harbor a non-replicating HIV-1 transgene and express chronic low-levels of multiple HIV-1 proteins. The
occasional but limited use of a drug is clinically distinct from escalated drug use, which is characterized by the
emergence of chronic compulsive drug-seeking and taking. Thus, we will use an established, state-of-the-art
paradigm of voluntary intravenous drug self-administration under long access (LgA) conditions that leads to
escalated (compulsive) METH intake in comparison to self-administration under short access (ShA) conditions,
which leads to a moderate and stable pattern of METH intake. The paradigm of escalated drug intake under
LgA conditions is highly relevant to the human substance use disorder (SUD) as it models all 7 of the criteria
for drug addiction in the Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV and 7 of the 11 criteria
in the DSM-V. We showed that HIV Tg rats self-administering METH in this paradigm display increased
compulsivity, neuroinflammation, and neural injury. The project will address the following vexing question about
persistent HIV infection in the CNS: what are the cell types and cell states that drive neuroinflammation,
neurodegeneration, and compulsive METH abuse in the setting of HIV that can reveal the pathogenic
mechanisms behind neuroHIV disease progression, virus expression and persistence? The overarching
hypothesis behind the present project is that the exploration of the gene regulatory network at the single cell
level will elucidate key mechanisms that underlie the effects of HIV and METH abuse and their detrimental
interactions on neuroHIV disease progression, virus expression, and virus persistence and will indicate novel
therapeutic targets for neuroinflammation, neurodegeneration, and compulsivity to take METH. To test this
hypothesis, we will use a validated systems biology strategy for the reconstruction and interrogation of
genome-wide gene regulatory networks to identify the gene network dysregulations associated with the effects
of HIV, compulsive METH use, and their interactions at single cell resolution gene profiling by single nucleus
RNA-Seq. Overall, this collaborative interdisciplinary proposal integrating single cell level transcriptomics,
state-of-the-art behavior methods in HIV Tg and wild-type rats, and computational strategies is expected to
identify novel mechanistic hypotheses that may lead to transformative new therapeutic concepts for substance
use disorder (SUD) in the HIV setting, and will establish key resources for the neuroHIV field to be made
publicly available through the SCORCH data coordination center.
总结
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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{{ truncateString('PIETRO P SANNA', 18)}}的其他基金
Single nucleus gene expression in moderate and compulsive opioid self-administration in a rodent model of HIV
HIV啮齿动物模型中度和强迫性阿片类药物自我给药的单核基因表达
- 批准号:
10682961 - 财政年份:2023
- 资助金额:
$ 133.83万 - 项目类别:
Transcriptional adaptations driving the intensification of alcohol-seeking in dependent rats undergoing prolonged abstinence
转录适应导致长期戒酒的依赖性大鼠对酒精的渴求加剧
- 批准号:
10540014 - 财政年份:2022
- 资助金额:
$ 133.83万 - 项目类别:
Single nucleus gene expression in moderate and compulsive drug self-administration in a rodent model of HIV
HIV啮齿动物模型中度和强迫性自我给药的单核基因表达
- 批准号:
10592330 - 财政年份:2022
- 资助金额:
$ 133.83万 - 项目类别:
Transcriptional adaptations driving the intensification of alcohol-seeking in dependent rats undergoing prolonged abstinence
转录适应导致长期戒酒的依赖性大鼠对酒精的渴求加剧
- 批准号:
10686229 - 财政年份:2022
- 资助金额:
$ 133.83万 - 项目类别:
An Innovative Approach to Identify Correctors of Metabolic Complications in HIV
一种识别 HIV 代谢并发症校正因子的创新方法
- 批准号:
10395011 - 财政年份:2021
- 资助金额:
$ 133.83万 - 项目类别:
Systems biology of RNA Modifications in HIV/AIDS and Substance Use Disorders
HIV/艾滋病和药物滥用疾病中 RNA 修饰的系统生物学
- 批准号:
10318620 - 财政年份:2018
- 资助金额:
$ 133.83万 - 项目类别:
Identification of small molecules for neurological complications of HIV and substance abuse comorbidity
鉴定治疗 HIV 神经并发症和药物滥用合并症的小分子
- 批准号:
10343707 - 财政年份:2018
- 资助金额:
$ 133.83万 - 项目类别:
Epigenetic regulation of alcohol tolerance and dependence by methyl CpG binding protein 2
甲基 CpG 结合蛋白 2 对酒精耐受性和依赖性的表观遗传调控
- 批准号:
9133075 - 财政年份:2017
- 资助金额:
$ 133.83万 - 项目类别:
Neural substrates of opiate-HIV interactions.
阿片类药物与艾滋病毒相互作用的神经基质。
- 批准号:
9344568 - 财政年份:2016
- 资助金额:
$ 133.83万 - 项目类别:
Cocaine abuse and plasticity in the lateral hypothalamus
可卡因滥用和外侧下丘脑的可塑性
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8989877 - 财政年份:2015
- 资助金额:
$ 133.83万 - 项目类别:
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