Defining molecular mechanisms by which stimulant evoked dopamine drives inflammation and neuronal dysfunction in neuroHIV
定义兴奋剂诱发多巴胺驱动神经艾滋病毒炎症和神经元功能障碍的分子机制
基本信息
- 批准号:10685160
- 负责人:
- 金额:$ 57.03万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-07-01 至 2025-06-30
- 项目状态:未结题
- 来源:
- 关键词:3-DimensionalATAC-seqAccelerationAddressAtlasesAutomobile DrivingBehavioralBiological AssayBrainCell Culture TechniquesCell SurvivalCellsChromatinClustered Regularly Interspaced Short Palindromic RepeatsCocaineCoculture TechniquesCognitiveCommunicationDataData CorrelationsDendritic SpinesDiseaseDisease ProgressionDopamineDopamine ReceptorElectrophysiology (science)EvaluationExposure toGene ExpressionGene Expression ProfileGenesGeneticHIVHIV InfectionsHealthHigh PrevalenceHumanImageImpaired cognitionImpairmentIn VitroInfectionInflammasomeInflammationInflammatoryInterventionKnowledgeMacrophageMediatingMembrane PotentialsMethamphetamineMicrogliaModelingMolecularMorphologyMyelogenousMyeloid CellsNeurobiologyNeurocognitive DeficitNeuroimmuneNeuronal DifferentiationNeuronal DysfunctionNeuronsNeuropathogenesisPathway interactionsPersonsPhasePhysiologicalPopulationProcessProductionProtocols documentationPublishingReceptor ActivationRestRiskStimulantSubstance abuse problemSystemSystemic diseaseTestingTranscription Factor AP-1Viralantiretroviral therapycell typecomorbidityconfocal imagingcytokinedensitydopaminergic neuronhigh throughput analysishigh throughput screeningin vitro activityinduced pluripotent stem cellknock-downmulti-electrode arraysneuroAIDSneuroinflammationneuropathologyneuropsychiatrynonhuman primatepandemic diseasepatch clamppharmacologicpreventreceptorresponsesingle-cell RNA sequencingstimulant exposurestimulant usetranscription factor
项目摘要
The HIV pandemic is increasingly driven by the spread of infection in vulnerable sub-populations with a relatively
high prevalence of substance abuse disorders (SUD), including the use of stimulants such as Methamphetamine
(Meth) and Cocaine (Coc). Stimulant use accelerates systemic disease, and can drive changes in
neuropathogenesis, increase risk neuropsychiatric comorbidities and accelerate cognitive decline, despite
effective ART. Despite the high prevalence of stimulant use among PLWH, the mechanisms by which stimulants
impact disease progression are poorly defined. This is particularly true in the CNS, as there are substantial
technical challenges involved in modeling microglial infection and interaction with neurons, as well as the
subsequent changes that this has on neuronal function. All stimulants increase CNS dopamine release, exposing
myeloid populations to highly elevated dopamine levels. Data indicate that it is the exposure to released
dopamine, rather than the stimulants themselves, which drives changes in microglial infection and function. Our
data support this, showing stimulant induced dopamine levels increase HIV entry and enhance myeloid
inflammation, increasing cytokine release, and NF-κB and NRLP3 inflammasome activity in vitro and in the NHP
CNS. Neuroinflammation driven by infected CNS myeloid populations is central to HIV neuropathogenesis in the
ART era, underlying the neuronal dysfunction and disruptions in neuroimmune communication that lead to
cognitive impairment and behavioral changes. We hypothesize that stimulant use exacerbates HIV-
associated microglial inflammation through dopamine receptor activation, leading to neuronal
dysfunction in neuroHIV. To address this, we propose to develop tractable, syngeneic co-cultures of human
iPSC-derived microglia (iMG) and iPSC-derived dopamine neurons (iDAN). Critically, these iDAN will release
dopamine in vitro in response to stimulant exposure. Co-cultures will be based on our existing protocols for iMG
and iDAN differentiation and will be developed and optimized for high-throughput analysis during the R61 phase.
During the R61, we will infect with HIV and treat with stimulants +/- ART, then use high content imaging, single
cell RNA-seq / ATAC-seq and Alphalisas to evaluate changes in viral dynamics (Aim 1b), gene expression and
chromatin accessibility (Aim 1c) and inflammation pathways (NF-κB, AP-1, STAT and NLRP3 activity, Aim 1d).
Using the R61 results as readouts, the R33 phase will use pharmacologic inhibition and CRISPR to identify the
specific dopamine receptors involved in each readout (Aim 2), and to examine neuronal function and
neuroimmune interaction (Aim 3) by evaluating; resting membrane potential and neuron firing rate with patch
clamp electrophysiology, dendritic spine density and morphology and microglial-neuronal contacts using
confocal imaging and Neurolucida360 analysis, and neuronal network activity using multielectrode arrays. This
will define specific dopamine receptors and microglial or neuronal functions that can be targeted to ameliorate
the impact of SUD on inflammation in PLWH by manipulating dopaminergic activity.
艾滋病毒的流行越来越多地是由于感染在弱势亚群体中的传播造成的
项目成果
期刊论文数量(0)
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会议论文数量(0)
专利数量(0)
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Peter Jesse Gaskill其他文献
Peter Jesse Gaskill的其他文献
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{{ truncateString('Peter Jesse Gaskill', 18)}}的其他基金
Benzodiazepine mediated mechanisms of transcriptional semi-quiescence in discrete myeloid populations
苯二氮卓介导离散骨髓细胞群转录半静止机制
- 批准号:
10700122 - 财政年份:2022
- 资助金额:
$ 57.03万 - 项目类别:
Benzodiazepine mediated mechanisms of transcriptional semi-quiescence in discrete myeloid populations
苯二氮卓介导离散骨髓细胞群转录半静止机制
- 批准号:
10573380 - 财政年份:2022
- 资助金额:
$ 57.03万 - 项目类别:
DAT-Psychostimulant mediated dopamine release increases macrophage IL-1beta production through NF-kB activation and inflammasome priming
DAT 精神兴奋剂介导的多巴胺释放通过 NF-kB 激活和炎症小体引发增加巨噬细胞 IL-1β 的产生
- 批准号:
9978381 - 财政年份:2020
- 资助金额:
$ 57.03万 - 项目类别:
Mechanisms of dopamine mediated increase in HIV infection of macrophages
多巴胺介导的巨噬细胞HIV感染增加的机制
- 批准号:
9333313 - 财政年份:2015
- 资助金额:
$ 57.03万 - 项目类别:
Dopamine Exacerbates NeuroAIDS by Activation of Macrophage Dopaminergic System
多巴胺通过激活巨噬细胞多巴胺能系统加剧神经艾滋病
- 批准号:
8040993 - 财政年份:2010
- 资助金额:
$ 57.03万 - 项目类别:
Dopamine Exacerbates NeuroAIDS by Activation of Macrophage Dopaminergic System
多巴胺通过激活巨噬细胞多巴胺能系统加剧神经艾滋病
- 批准号:
8637953 - 财政年份:2010
- 资助金额:
$ 57.03万 - 项目类别:
Dopamine Exacerbates NeuroAIDS by Activation of Macrophage Dopaminergic System
多巴胺通过激活巨噬细胞多巴胺能系统加剧神经艾滋病
- 批准号:
9185430 - 财政年份:2010
- 资助金额:
$ 57.03万 - 项目类别:
Dopamine Exacerbates NeuroAIDS by Activation of Macrophage Dopaminergic System
多巴胺通过激活巨噬细胞多巴胺能系统加剧神经艾滋病
- 批准号:
8242055 - 财政年份:2010
- 资助金额:
$ 57.03万 - 项目类别:
Dopamine Exacerbates NeuroAIDS by Activation of Macrophage Dopaminergic System
多巴胺通过激活巨噬细胞多巴胺能系统加剧神经艾滋病
- 批准号:
8446427 - 财政年份:2010
- 资助金额:
$ 57.03万 - 项目类别:
Dopamine Exacerbates NeuroAIDS by Activation of Macrophage Dopaminergic System
多巴胺通过激活巨噬细胞多巴胺能系统加剧神经艾滋病
- 批准号:
7929994 - 财政年份:2010
- 资助金额:
$ 57.03万 - 项目类别:
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