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。
基本信息
- 批准号:9344568
- 负责人:
- 金额:$ 58.1万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-09-15 至 2021-07-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAlcohol or Other Drugs useAreaAstrocytesAutomobile DrivingBehaviorBehavioralBrain regionCaliforniaCancer BiologyCellsCentral Nervous System DiseasesClinicalClustered Regularly Interspaced Short Palindromic RepeatsCognitionCognitiveComorbidityContractsData SetDiseaseDisease ProgressionDown-RegulationDrug AddictionDrug abuseExposure toFluorescence-Activated Cell SortingGene ExpressionGene Expression ProfileGene Expression ProfilingGenesHIVHIV InfectionsHIV-1HIV-associated neurocognitive disorderHeadHeroinHeroin AbuseHumanImmuneImpaired cognitionIndividualInjuryIntakeIntravenousInvestigationLeadMeasuresMediatingMedicineMental DepressionMicrogliaModelingMolecularMolecular AnalysisMolecular NeurobiologyMolecular ProfilingMusNational NeuroAids Tissue ConsortiumNerve DegenerationNeuraxisNeurobiologyNeurogliaNeurologicNeuronal DysfunctionNeuronsNeuropsychologyOpiatesPathogenesisPathologicPathway interactionsPatientsPatternPharmaceutical PreparationsPhenotypePopulationPrefrontal CortexPremature aging syndromeProcessProteinsRattusRecording of previous eventsRegulator GenesResearch PersonnelResearch PriorityRiskRodentRoleSample SizeSelf AdministrationSmall Interfering RNASubstance AddictionSubstance of AbuseSystems BiologyTestingTherapeuticTranscriptTransgenic OrganismsUniversitiesUrsidae FamilyViral Vectorantiretroviral therapybasecell typecollegedrug of abusegenome-wideimprovedinjection drug usemutantneuroAIDSneuroinflammationneuropathologynew therapeutic targetnon-compliancenoveloverexpressionpandemic diseasepublic health relevancereconstructionrelating to nervous systemtranscriptome sequencingviral transmissionvirology
项目摘要
Abstract
Despite the introduction of combination antiretroviral therapy (cART), central nervous system (CNS)
disease remains a significant challenge in patients with HIV. The abuse of drugs such as heroin is associated
with treatment non-compliance, greater risk of viral transmission, and more rapid clinical progression of HIV
disease. The overarching hypothesis behind the present project is that the analysis of molecular profiles of
neuronal and glia cells will reveal key genes that are dysregulated by HIV and by the interaction of HIV with
heroin abuse, resulting in cognitive impairments and depression. Their identification will point to transformative
new mechanistic hypotheses on neuroAIDS pathogenesis and, consequently, to novel therapeutic targets to
improve neuropsychological functioning in people with HIV.
To test the present hypothesis, we propose to use validated systems biology strategies for the reconstruction
and interrogation of a genome-scale integrated gene regulatory network (interactome) using gene profiles by
RNA sequencing (RNA-Seq) from HIV-1 transgenic (Tg) and wild-type rats in a state-of-the-art paradigm of
voluntary intravenous drug self-administration under long access (LgA) conditions, which leads to dependent
heroin intake, and short access (ShA) conditions, which is characterized by a non-dependent, more
“recreational” pattern of heroin use. Because of the pivotal roles of glia cells in the pathogenesis of neuronal
dysfunction in the setting of neuroAIDS as well as in neuroinflammatory processes induced by drugs of abuse
such as opiates, for the proposed interactome we will profile neurons, astrocytes and microglia purified by
fluorescence-activated cell sorting (FACS) from key brain regions involved in the effects of HIV and drug
dependence. We will interrogate the interactome to identify the gene network dysregulations driven by the
interaction of HIV and dependent and non-dependent heroin intake. Specific mechanistic hypotheses derived
from interactome reconstruction and interrogation will be tested with viral vector-mediated overexpression or
down-regulation and genetically modified rats and mice in conjunction with additional rounds of gene
expression profiling, behavioral analyses and neuropathology analyses to elucidate their contributions to the
effects of HIV and heroin on cognition, depression-like behavior, and neurodegeneration.
Central nervous system (CNS) disease remains a pressing problem in the HIV pandemic despite the
introduction of cART. Injection drug use is associated with treatment non-compliance, greater risk of viral
transmission, and more rapid clinical progression of HIV disease. The present proposal will bring to bear a
systems biology approach to identify and test new mechanistic hypotheses that may lead to novel
transformative therapeutic concepts to improve neuropsychological functioning in people with HIV.
摘要
尽管引入了联合抗逆转录病毒治疗(cART),中枢神经系统(CNS)
疾病仍然是艾滋病毒患者面临的重大挑战。海洛因等毒品的滥用与
治疗不依从、病毒传播风险更大、HIV临床进展更快
疾病本项目背后的首要假设是,
神经元和神经胶质细胞将揭示艾滋病毒和艾滋病毒与
海洛因滥用,导致认知障碍和抑郁症。他们的身份将指向变革
关于神经艾滋病发病机制的新机制假说,并因此涉及新的治疗靶点,
改善HIV感染者的神经心理功能。
为了检验目前的假设,我们建议使用经过验证的系统生物学策略进行重建
和使用基因谱的基因组规模的整合基因调控网络(相互作用组)的询问,
以最先进的方法对HIV-1转基因(Tg)和野生型大鼠进行RNA测序(RNA-Seq),
在长期使用(LgA)条件下自愿静脉内药物自我给药,导致依赖性
海洛因摄入量,和短期访问(ShA)的条件,其特点是非依赖性,更
“消遣性”吸食海洛因由于神经胶质细胞在神经元损伤的发病机制中的关键作用,
在神经艾滋病以及滥用药物引起的神经炎症过程中的功能障碍
如阿片类药物,对于所提出的相互作用组,我们将分析神经元、星形胶质细胞和小胶质细胞,
从涉及HIV和药物作用的关键脑区进行荧光激活细胞分选(FACS)
依赖我们将询问相互作用组,以确定基因网络失调驱动的
艾滋病毒与依赖性和非依赖性海洛因摄入的相互作用。具体的机制假设推导
将用病毒载体介导的过表达或
下调和转基因的大鼠和小鼠与额外的基因轮
表达谱分析、行为分析和神经病理学分析,以阐明它们对
HIV和海洛因对认知、抑郁样行为和神经退行性变的影响。
中枢神经系统(CNS)疾病仍然是艾滋病毒流行的一个紧迫问题,尽管
CART的引入注射药物使用与治疗不依从性相关,病毒感染风险更大
传播,以及更快的艾滋病毒疾病的临床进展。目前的建议将带来一个
系统生物学方法,以确定和测试新的机制假设,可能会导致新的
变革性的治疗概念,以改善艾滋病毒感染者的神经心理功能。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
PIETRO P SANNA其他文献
PIETRO P SANNA的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ 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:
$ 58.1万 - 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:
$ 58.1万 - 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:
$ 58.1万 - 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:
10454706 - 财政年份:2022
- 资助金额:
$ 58.1万 - 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:
$ 58.1万 - 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:
$ 58.1万 - 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:
$ 58.1万 - 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:
$ 58.1万 - 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:
$ 58.1万 - 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
- 批准号:
8989877 - 财政年份:2015
- 资助金额:
$ 58.1万 - 项目类别: