Chloride channel-dependent mechanisms of opiate and HIV-induced synaptodendritic injury
阿片类药物和 HIV 诱导的突触树突损伤的氯离子通道依赖性机制
基本信息
- 批准号:10704734
- 负责人:
- 金额:$ 23.29万
- 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:2022-09-15 至 2024-08-31
- 项目状态:已结题
- 来源:
- 关键词:AMPA ReceptorsAcuteAffectAfferent NeuronsAstrocytesBehavioralBlood - brain barrier anatomyBrainBuffersCLC-1 channelCell LineCellsChloride ChannelsComplexCorpus striatum structureCouplingDataDisinhibitionDissociationDopamine D1 ReceptorDrug TargetingElectrophysiology (science)EquilibriumExposure toFunctional disorderGeneticGlutamatesGlycine ReceptorsHIVHIV Envelope Protein gp120HIV-1HIV-associated neurocognitive disorderHomeostasisImmunosuppressionIn VitroInjuryInterneuronsInterventionIon ChannelLong-Term EffectsMediatingMembraneMicrogliaModelingMolecularMolecular BiologyMorphineMorphologyN-Methyl-D-Aspartate ReceptorsNeurogliaNeuronal InjuryNeuronsOpioidPathologyPeripheralPersonsRegulationRoleSignal TransductionSiteSliceSourceSynapsesSystemTechniquesTestingTherapeuticTimeTransgenic Micebehavioral outcomecentral nervous system injuryconfocal imagingcytokinedriving forceexcitotoxicitygain of functiongamma-Aminobutyric Acidgenetic approachin vivoloss of functionmouse modelnervous system disorderneuroAIDSneuroinflammationneuron lossneuronal excitabilityneurotoxicnovelopioid abuseopioid use disorderpharmacologicpostsynapticpresynapticsymportersynaptic inhibitionvoltage
项目摘要
Opioid use disorder (OUD) in people infected with HIV-1 (PWH) exacerbates the pathobiology of neuroHIV and
HIV-associated neurocognitive disorder (HAND) via complex mechanisms involving direct peripheral (e.g.,
immune suppression) and CNS (e.g., neuroinflammation, blood-brain barrier damage, and neuronal injury)
effects. Although glutamatergic excitotoxicity remains the major driving force in HIV-dependent neuronal injury,
emerging evidence from our lab indicates that the loss of inhibitory GABAergic control and [Cl−]i homeostasis
not only contributes to a loss of inhibition, but also increases the excitatory/neurotoxic effects of glutamate at
NMDA and AMPA receptors. This proposal directly tests the assumption that [Cl−]i-dependent net losses of
neuronal inhibition will increase excitation and promote excitotoxic. In mature neurons, intracellular Cl−
concentration ([Cl−]i) is dynamically regulated by membrane ion channels (GABAA and glycine receptors) and
Cl− channels and transporters. By controlling [Cl−]i, these channels and transporters regulate the Cl−
equilibrium potential (ECl) and neuronal inhibition and we have already shown the KCC2 loss-of-function in
OUD/neuroHIV models leads to [Cl−]i increases, elevated ECl, and excitotoxicity. We discovered a previously
unidentified a ClC-1-like voltage-dependent Cl− channel that differentially regulates the excitability of dopamine
receptor D1- and D2- expressing (D1 and D2, respectively) striatal medium spiny neurons (MSNs) and is
disrupted by opioids and HIV Tat. We hypothesize that opioids and HIV-1 disrupt [Cl−]i, homeostasis via a
voltage-gated ClC Cl− channel resulting in synaptodendritic injury. This hypothesis will be tested in the
following specific aims and if confirmed will be a conceptual shift in our understanding of how opioids and HIV
contribute to excitotoxicity. Aim 1 will identify the mechanisms by which opioids and HIV dysregulate voltage-
dependent ClC-1 channels and Cl− homeostasis in vitro. Our preliminary findings suggest that ClC-1
significantly affects voltage-dependent Cl− currents in D1 and D2 MSNs. The extent to which ClC-1 mediates
the HIV and opioid-induced pathology will be explored using gain-of-function, loss-of-function strategies, and
confirmed in vitro and in vivo/ex vivo using electrophysiologic, pharmacologic, and genetic approaches at the
cell and molecular levels. Aim 2. Establish to what extent ClC-1 modulation contributes to the synaptodendritic
injury caused by opioids and HIV-induced dysregulation of Cl− homeostasis. We predict that the dysregulation
of [Cl−]i homeostasis amplifies synaptodendritic injury in MSNs in OUD/neuroHIV models. Since ClC-1 can be a
novel source of activity-dependent Cl− entry, we also predict that opioids and HIV Tat cause neuronal injury via
a complex mechanism involving ClC-1 modulation and, thus, synaptic disinhibition. This project will test
whether opioids and HIV dysregulate [Cl−]i homeostasis and cause neuronal injury via ClC-1. If ClC-1 is
confirmed to be that target, as preliminary evidence indicates, this will be a conceptual shift in our
understanding of how opioids and HIV contribute to excitotoxicity.
HIV-1(PWH)感染者的阿片类药物使用障碍(OUD)加剧了神经HIV的病理生物学,
通过涉及直接外周(例如,
免疫抑制)和CNS(例如,神经炎症、血脑屏障损伤和神经元损伤)
方面的影响.虽然多巴胺能兴奋毒性仍然是HIV依赖性神经元损伤的主要驱动力,
我们实验室的新证据表明,抑制性GABA能控制和[Cl−]i稳态的丧失
不仅导致抑制作用的丧失,而且还增加谷氨酸的兴奋性/神经毒性作用,
NMDA和AMPA受体。这个提议直接检验了[Cl−] i依赖的净损失的假设,
神经元抑制将增加兴奋并促进兴奋毒性。在成熟神经元中,细胞内Cl−
浓度([Cl−]i)由膜离子通道(GABAA和甘氨酸受体)动态调节,
Cl−通道和转运蛋白。通过控制[Cl−]i,这些通道和转运蛋白调节Cl−
平衡电位(EC 1)和神经元抑制,我们已经表明,KCC 2功能丧失,
OUD/neuroHIV模型导致[Cl−]i增加,ECl升高和兴奋性毒性。我们之前发现了一个
鉴定了一种ClC-1样电压依赖性Cl−通道,其差异调节多巴胺的兴奋性,
受体D1和D2表达(分别为D1和D2)纹状体中型棘神经元(MSN),
被阿片类药物和艾滋病病毒达特破坏。我们假设阿片类药物和HIV-1通过一种新的途径破坏[Cl-]i的稳态。
电压门控ClC Cl−通道导致突触树突损伤。这一假设将在
如果得到证实,这将是我们对阿片类药物和艾滋病毒如何相互作用的理解的概念转变。
导致兴奋性毒性。目标1将确定阿片类药物和艾滋病毒失调电压的机制,
依赖性ClC-1通道和体外Cl−稳态。我们的初步发现表明,ClC-1
显著影响D1和D2 MSN中的电压依赖性Cl−电流。ClC-1介导的程度
HIV和阿片类药物诱导的病理学将使用功能获得、功能丧失策略进行探索,
使用电生理学、药理学和遗传学方法在体外和体内/离体证实,
细胞和分子水平。目标2.确定ClC-1调节在多大程度上有助于突触树突
阿片类药物引起的损伤和HIV诱导的Cl−稳态失调。我们预测,
[Cl−]i稳态的增强在OUD/neuroHIV模型中MSN中的突触树突损伤。由于ClC-1可以是
活性依赖性Cl−进入的新来源,我们还预测阿片类药物和HIV达特通过以下途径引起神经元损伤:
这是一种复杂的机制,涉及C1 C-1调节,因此,突触去抑制。该项目将测试
阿片类药物和HIV是否通过ClC-1调节[Cl−]i稳态并引起神经元损伤。如果ClC-1是
初步证据表明,这将是我们在概念上的转变。
了解阿片类药物和艾滋病毒如何导致兴奋性毒性。
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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Kurt F Hauser其他文献
Kurt F Hauser的其他文献
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{{ truncateString('Kurt F Hauser', 18)}}的其他基金
Chloride channel-dependent mechanisms of opiate and HIV-induced synaptodendritic injury
阿片类药物和 HIV 诱导的突触树突损伤的氯离子通道依赖性机制
- 批准号:
10548312 - 财政年份:2022
- 资助金额:
$ 23.29万 - 项目类别:
Innovative therapeutic approaches to address excitotoxic CNS/neuronal damage in opioid-neuroHIV comorbidity
解决阿片类药物-神经艾滋病毒合并症中的兴奋性中枢神经系统/神经元损伤的创新治疗方法
- 批准号:
10573827 - 财政年份:2022
- 资助金额:
$ 23.29万 - 项目类别:
Innovative therapeutic approaches to address excitotoxic CNS/neuronal damage in opioid-neuroHIV comorbidity
解决阿片类药物-神经艾滋病毒合并症中的兴奋性中枢神经系统/神经元损伤的创新治疗方法
- 批准号:
10684110 - 财政年份:2022
- 资助金额:
$ 23.29万 - 项目类别:
Selective vulnerability of discrete neural circuits in the striatum to HIV-opiate comorbidity
纹状体中离散神经回路对艾滋病毒-阿片类共病的选择性脆弱性
- 批准号:
10317037 - 财政年份:2018
- 资助金额:
$ 23.29万 - 项目类别:
HIV opiate interactions in white matter pathology
HIV阿片类药物在白质病理学中的相互作用
- 批准号:
9419501 - 财政年份:2017
- 资助金额:
$ 23.29万 - 项目类别:
Bivalent Ligands as Chemical Probes to Study Opioid Abuse-enhanced HIV Infection
二价配体作为化学探针研究阿片类药物滥用增强的 HIV 感染
- 批准号:
9924466 - 财政年份:2017
- 资助金额:
$ 23.29万 - 项目类别:
HIV opiate interactions in white matter pathology
HIV阿片类药物在白质病理学中的相互作用
- 批准号:
10189540 - 财政年份:2017
- 资助金额:
$ 23.29万 - 项目类别:
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