Functional impact of antiretroviral drugs on human neuronal subtypes

项目总结 抗逆转录病毒疗法(Art)已被证明在降低艾滋病毒感染者的病毒载量方面非常成功。 但存在潜在的非靶点效应，可能导致神经认知的出现 精神障碍和/或精神症状。为了更好地预测哪些人可能会受到副作用的影响 我们需要更好地从机制上理解抗逆转录病毒药物如何影响人类中枢神经系统 神经系统。尽管动物模型和尸检分析提供了关键信息，但其他 需要互补的方法来弥合这些模型之间的差距，并确定生物标志物和 艺术的细胞签名。最近，产生人类诱导多能性的方法学的引入 干细胞(ISPCS)允许在人体内产生任何类型的可再生资源。为 尤其是神经和精神障碍，这种方法有望促进受控 利用人类神经元了解遗传和环境扰动如何改变的研究 细胞功能并在神经回路中引发广泛的病理。该项目旨在评估 几种抗逆转录病毒药物对不同亚型人类神经元的分子、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效果的全面概况 皮质谷氨酸能神经元和GABA能神经元均为单细胞水平。成功完成这些任务 实验将为研究界生成单细胞转录和表观基因组数据集 可能导致识别ART药物的细胞类型特定的新途径和靶点。这个平台将 也为研究抗逆转录病毒药物的个体变异性和潜在的 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.