Functional impact of antiretroviral drugs on human neuronal subtypes

抗逆转录病毒药物对人类神经元亚型的功能影响

基本信息

批准号：
10025266
负责人：
Kimberly Christian
金额：
$ 20.25万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-26 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10025266
关键词：
ATAC-seq Acquired Immunodeficiency Syndrome Acute Affect Animal Model Anti-Retroviral Agents Autopsy Behavioral Bioinformatics Biological Markers Biological Process Cell physiology Cells Chronic Clinic Cognition Disorders Communities Data Data Set Development Diagnostic Drug Exposure Electrophysiology (science)Epigenetic Process Evaluation Exposure to Foundations Functional disorder Generations Genetic Genetic Variation Glutamates HIV HIV Infections HIV-associated neurocognitive disorder Human Human body Impaired cognition Individual Individual Differences Investigation Knowledge Lead Link Measures Mental Depression Mental disorders Methodology Modeling Molecular Neuraxis Neurobehavioral Manifestations Neurocognitive Deficit Neuronal Dysfunction Neurons Neurotransmitters Outcome Pathology Pathway interactions Patients Pharmaceutical Preparations Pharmacologic Substance Pharmacotherapy Physiological Population Pre-Clinical Model Property Protocols documentation Quality of life Recording of previous events Regimen Research Resources Risk Sleeplessness Structure Synapses System Techniques Technology Testing Tissues Translating Viral Viral Load result antiretroviral therapy base behavioral outcome behavioral response cell fate specification cell type chromatin modification cognitive function comorbidity data integration density design drug development epigenomics experience experimental study genome-wide individual patient individual variation induced pluripotent stem cell medication safety multi-electrode arrays nervous system disorder neural circuit novel novel strategies optimal treatments patient subsets prevent psychiatric symptom psychotic symptoms relating to nervous system response safety testing screening side effect tool transcriptome sequencing transcriptomics viral transmission

项目摘要

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.

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。为了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。