Integrating preclinical models to develop converging mechanistic data in co-occurring HIV and substance use

整合临床前模型以开发同时发生的艾滋病毒和药物使用的趋同机制数据

• 批准号: 10055935
• 负责人: JACQUELINE M BARKER
• 金额: $ 227.06万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10055935
• 关键词: Address; Adult; Alcohol or Other Drugs use; Astrocytes; Behavior; Behavioral; Biological; Calcium Signaling; Cells; Central Nervous System Infections; Chronic; Cocaine; Collaborations; Data; Development; Drug Exposure; Drug Regulations; Drug usage; Exposure to; Fiber; Gene Expression; Glutamates; HIV; HIV Infections; HIV-associated neurocognitive disorder; Human; Immunology; In Situ Hybridization; Individual; Industry Standard; Infection; Learning; Literature; Medial; Mediator of activation protein; Microglia; Modeling; Mus; Neurobiology; Neurons; Nucleus Accumbens; Patients; Pharmaceutical Preparations; Pharmacology; Population; Pre-Clinical Model; Prefrontal Cortex; Relapse; Research; Rewards; Role; Specificity; Substance Use Disorder; System; Systems Biology; Tenofovir; Testing; United States; Virus; Wild Type Mouse; adverse outcome; antiretroviral therapy; cell type; cocaine use; combinatorial; comorbidity; drug discovery; emtricitabine; humanized mouse; mortality; mouse model; novel; patient population; pre-clinical; prevent; protein expression; scaffold; standard care; success; therapy development; tool; uptake

Substance use disorders are highly comorbid with HIV infection, with nearly 25% of individuals with HIV needing treatment. With the success of combinatorial antiretroviral therapies (cART), HIV-associated mortality has substantially declined. This has resulted in a growing population of chronically HIV-infected and cART treated adults in the United States. Both HIV infection and cART may interact with drug exposure to alter neurobiology, thus creating a behaviorally and biologically distinct condition and requiring novel, targeted pharmacotherapeutic strategies to reduce the compulsive drug use and high relapse propensity that characterize substance use disorders. The corticostriatal glutamate system is a key regulator of these forms of behavioral inflexibility. Projections from the medial prefrontal cortex to the nucleus accumbens are critical mediators of reinstatement of drug seeking, a model of relapse, and the inability to terminate drug seeking despite adverse consequences, a model of compulsivity. A growing literature in both HIV patient populations and preclinical models has identified infection-induced alterations in the corticostriatal glutamate system as a contributor to HIV-associated neurocognitive disorders. Despite this, a robust characterization of corticostriatal glutamate system alterations in HIV infection and cART treatment, with circuit- and cell-type specificity, is lacking. We will capitalize on the advent of new mouse models of HIV infection and perform studies in parallel in (1) a humanized mouse model that successfully develops human-like microglia, thus enabling progressive central nervous system infection with HIV, and (2) wild-type mice infected with a chimeric virus – EcoHIV. To determine whether current industry standards of treatment impact behavior or glutamate system biology independently or in combination, a subset of mice will receive chronic bictegravir, emtricitabine, and tenofovir alafenamide (B/F/TAF) treatment. This research will use multiplexed in situ hybridization to test the hypothesis that gene and protein expression are altered in glutamate neurons and astrocyte populations in mouse models of HIV infection and cART. We will also test the hypothesis that HIV infection and B/F/TAF interact to regulate astrocyte and neuron calcium signaling during cocaine reward learning, cocaine reinstatement, and compulsive-like cocaine seeking via simultaneous fiber photometric assessment in corticostriatal astrocytes and neurons. To demonstrate a role for gliotransmission and glutamatergic corticostriatal neuron activity in reducing compulsive-like or relapse-related cocaine seeking in mice, we will use cell- and circuit-specific chemogenetic manipulations. Finally, we will use novel and preclinically-validated pharmacological tools for regulating glutamate release and uptake in humanized, HIV-infected and EcoHIV-infected mice to determine whether pharmacological strategies to reduce compulsivity and relapse are similarly effective in infected and B/F/TAF-treated states. My lab will address this unmet need through collaboration with leaders in the immunology, HIV, and drug discovery fields, enabling us to provide thorough, convergent data on corticostriatal glutamate regulation of drug seeking in HIV infection.

物质使用障碍与HIV感染高度共病，近25%的HIV感染者需要 治疗随着联合抗逆转录病毒疗法（cART）的成功， 大幅下降。这导致慢性艾滋病毒感染者和接受cART治疗的人口不断增加 成年人在美国。HIV感染和cART都可能与药物暴露相互作用，改变神经生物学， 从而产生行为和生物学上不同的病症，并需要新的靶向药物 减少作为物质使用特征的强迫性药物使用和高复发倾向的战略 紊乱皮质纹状体谷氨酸系统是这些形式的行为稳定性的关键调节器。 从内侧前额叶皮质到脑桥核的投射是恢复的关键介质 寻求毒品，复吸的模式，以及尽管有不良后果但无法终止寻求毒品， 一个强迫症的典型越来越多的关于HIV患者人群和临床前模型的文献已经确定， 感染诱导的皮质纹状体谷氨酸系统改变是艾滋病毒相关性的贡献者 神经认知障碍尽管如此，皮质纹状体谷氨酸系统改变的一个强有力的表征 在艾滋病毒感染和cART治疗中缺乏具有回路和细胞类型特异性的方法。我们将利用 新的HIV感染小鼠模型的出现，并在（1）人源化小鼠模型中进行平行研究 成功地开发出类似人类的小胶质细胞，从而使渐进性中枢神经系统感染， HIV，和（2）感染嵌合病毒- EcoHIV的野生型小鼠。以确定当前行业是否 治疗标准影响行为或谷氨酸系统生物学独立或组合， 的小鼠将接受慢性比替拉韦、恩曲他滨和替诺福韦艾拉酚胺（B/F/TAF）治疗。这 研究将使用多重原位杂交来检验基因和蛋白质表达是 在HIV感染和cART的小鼠模型中，谷氨酸神经元和星形胶质细胞群体发生了改变。我们还将 检验HIV感染和B/F/TAF相互作用调节星形胶质细胞和神经元钙信号传导的假设 在可卡因奖励学习、可卡因恢复和强迫性可卡因寻求过程中， 皮质纹状体星形胶质细胞和神经元的纤维光度评估。为了证明一个角色， 神经胶质传递和多巴胺能皮质纹状体神经元活动在减少强迫样或复发相关的 为了在小鼠中寻找可卡因，我们将使用细胞和回路特异性化学遗传学操作。最后，我们将使用 用于调节谷氨酸释放和摄取的新的和临床前验证的药理学工具 人源化，HIV感染和EcoHIV感染的小鼠，以确定是否有药理学策略，以减少 强迫症和复发在感染和B/F/TAF治疗状态中同样有效。我的实验室会解决这个问题 通过与免疫学、艾滋病毒和药物发现领域的领导者合作， 为HIV感染中皮质纹状体谷氨酸对药物寻求的调节提供全面、集中的数据。