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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.

项目总结