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

基本信息

  • 批准号:
    10684110
  • 负责人:
  • 金额:
    $ 67.87万
  • 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:
    2022-08-15 至 2027-05-31
  • 项目状态:
    未结题

项目摘要

Injection drug use increases the probability of contracting HIV, and opioid use disorder (OUD) accelerates HIV- 1 infection through immune suppression and direct CNS actions. Glutamatergic excitotoxicity is a major factor in HIV-dependent CNS injury, but emerging evidence also suggests a loss of inhibitory GABAergic function in neuroHIV. The parallel loss of Cl− homeostasis and GABAergic tone will worsen excitatory outcomes since ‘disinhibition’ results in net excitation. If this is true, then interventions that protect inhibitory systems are predicted to at least partially negate ‘excitotoxic’ effects of HIV. KCC2 is the main transporter responsible for maintaining [Cl−]i homeostasis and GABAergic function in the adult CNS and is the focus of proposed studies. Although the idea of disinhibition as a driving force is embraced for other neurological disorders (e.g., autism, certain epilepsies, opioid dependence, traumatic brain/spinal cord injury), it represents a conceptual shift about mechanisms underlying synaptodendritic dysfunction in neuroHIV. The Cl− concentration inside neurons ([Cl−]i) is small and the Cl− reversal potential (ECl) is close to the resting membrane potential. Thus, minor changes in [Cl−]i can greatly affect the strength and polarity of inhibitory (e.g., GABAA) transmission. NKCC1 (Cl− uptake) and KCC2 (Cl− efflux) co-transporters are key regulators of [Cl−]i, and KCC2 expression/function is essential for adult neuron survival. Their balance can be regulated by cytokines/trophic factors (e.g., BDNF) from glia, therapeutically (CLP290), genetically, and by opioids. Importantly, we find that increasing KCC2 levels/function strongly protects against exposure to Tat, gp120, infectious HIV, and opioids in human and mouse neurons. In vivo, maintaining KCC2 phosphorylation can normalize KCC2 localization in Drd2-expressing striatal medium spiny neuron (MSN) cell membranes and reverse motor deficits due to HIV-1 Tat. Aim 1 uses in vitro models including iPSC MSNs, infective HIV, and optical electrophysiology to identify mechanisms by which HIV and/or opioids alter [Cl−]i homeostasis, dysregulate D1/D2 MSN excitability, how this triggers synaptodendritic injury, and protective strategies. Despite its fundamental importance, the role of KCC2 in excitatory/inhibitory (E-I) imbalances and altered ECl and EGABA have never been explored in the context of HIV/OUD. Aim 2 extends the studies in vivo/ex vivo. 2 transgenic models (Tat+/-, HIVTg26) that both mimic clinical pathology with considerable fidelity are crossed with transgenic mice expressing Drd1a-tdTomato (D1) and Drd2-eGFP (D2) to identify both striatal MSN populations. Acute (2 wk) and chronic (8 wk) HIV/Tat exposure times are examined; separate cohorts of mice (both sexes) receive concurrent, ramping exposure to morphine (s.c.). Comprehensive studies of [Cl−]i regulation in MSNs (gramicidin-perforated patch physiology), synaptodendritic injury, and behavior related to striatal function are performed ± the KCC2 enhancer prodrug CLP290 as an intervention strategy. Alternative [Cl−]i regulation through NKCC1, TMEM16A, and CLC-1 are also tested. GCaMP8f expression in D1/D2 MSNs in awake, behaving mice links striatal output activity to behavioral change (Inscopix miniscopes).
注射吸毒增加了感染艾滋病毒的可能性,阿片类药物使用障碍(OUD)加速了艾滋病毒的传播

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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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:
    10704734
  • 财政年份:
    2022
  • 资助金额:
    $ 67.87万
  • 项目类别:
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:
    $ 67.87万
  • 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:
    $ 67.87万
  • 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:
    $ 67.87万
  • 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:
    $ 67.87万
  • 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:
    $ 67.87万
  • 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:
    $ 67.87万
  • 项目类别:
S1P Receptor Mechanisms in Neuropathic Pain
神经性疼痛中的 S1P 受体机制
  • 批准号:
    9750825
  • 财政年份:
    2015
  • 资助金额:
    $ 67.87万
  • 项目类别:
S1P Receptor Mechanisms in Neuropathic Pain
神经性疼痛中的 S1P 受体机制
  • 批准号:
    9775762
  • 财政年份:
    2015
  • 资助金额:
    $ 67.87万
  • 项目类别:
Chemical Probes on NeuroAIDS
神经艾滋病化学探针
  • 批准号:
    8789943
  • 财政年份:
    2014
  • 资助金额:
    $ 67.87万
  • 项目类别:

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