Functional impact of antiretroviral drugs on human neuronal subtypes

项目概要 事实证明，抗逆转录病毒疗法 (ART) 在降低 HIV 感染者的病毒载量方面非常成功 个体，但存在潜在的脱靶效应，可能导致神经认知的出现 损伤和/或精神症状。为了更好地预测哪些人可能容易受到侧面影响 影响，我们需要更好地了解 ART 药物如何影响人体中枢 神经系统。尽管动物模型和尸检分析提供了关键信息，但额外的 需要补充方法来弥合这些模型之间的差距并识别生物标志物和 ART 的细胞特征。最近，引入了产生人类诱导多能性的方法 干细胞（iSPC）可以产生人体内任何细胞类型的可再生资源。对于 特别是神经和精神疾病，这种方法有望促进控制 使用人类神经元进行研究以了解遗传和环境扰动如何改变 细胞功能并引发神经回路中广泛的病理学。该项目旨在评估 几种 ART 药物对人类神经元不同亚型的分子、细胞和功能影响。我们 将使用多种方法的组合来生成这些药物的作用的全面概况 皮质谷氨酸能神经元和 GABA 能神经元的单细胞水平。顺利完成这些 实验将为研究界生成单细胞转录组和表观基因组数据集 可能导致识别细胞类型特异性的新途径和 ART 药物的靶点。该平台将 还为研究个体对 ART 药物反应的变异性和潜在的 指导治疗决策的诊断工具。

PROJECT SUMMARY Antiretroviral therapy (ART) has proven remarkably successful in decreasing the viral load in HIV-infected individuals but there are potential off-target effects that can result in the emergence of neurocognitive impairments and/or psychiatric symptoms. To better predict which individuals may be susceptible to side effects, we need a better mechanistic understanding of how ART drugs may be affecting the human central nervous system. Although animal models and postmortem analyses provide critical information, additional complementary approaches are needed to bridge the gap between these models and identify biomarkers and cellular signatures of ART. Recently, the introduction of methodology to generate human induced pluripotent stem cells (iSPCs) allows for the generation of a renewable resource of any cell type in human body. For neurological and psychiatric disorders in particular, this approach holds the promise of facilitating controlled investigations using human neurons to understand how genetic and environmental perturbations may alter cellular function and trigger widespread pathology in neural circuits. This project is designed to evaluate the molecular, cellular, and functional impact of several ART drugs on different subtypes of human neurons. We will use a combination of approaches to generate a comprehensive profile of the effects of these drugs at the single cell level in both cortical glutamatergic neurons and GABAergic neurons. Successful completion of these experiments will generate single cell transcriptomic and epigenomic datasets for the research community and could lead to the identification of cell-type specific novel pathways and targets of ART drugs. This platform will also provide a foundation to investigate individual variability in response to ART drugs and a potential diagnostic tool to guide treatment decisions.