Modeling drugs of abuse-HIV interactions using iPSC-derived human cerebral organoids

使用 iPSC 衍生的人脑类器官模拟药物滥用与 HIV 相互作用

基本信息

批准号：
10491704
负责人：
Vez REPUNTE-CANONIGO
金额：
$ 87.11万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-30 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10491704
关键词：
AIDS/HIV problem Alcohol abuse Alzheimer&apos s Disease Anti-Retroviral Agents Astrocytes Automobile Driving CRISPR/Cas technology Cells Cerebrum Closure by clamp Computing Methodologies Data Disease Disease Progression Dissection Drug Modelings Drug abuse Electrophysiology (science)Exposure to Gene Expression Gene Expression Profiling Gene Expression Regulation Genomic approach HIV HIV Envelope Protein gp120 Human Inflammation Injury Integration Host Factors Lead Light Literature Mediator of activation protein Methamphetamine Microglia Modeling Monitor Morphine Nerve Degeneration Neuraxis Neurodegenerative Disorders Neurons Neuropathogenesis Neuropsychology Opioid Organoids Pathogenesis Persons Pharmaceutical Preparations Preparation Property Proviruses Regulation Regulator Genes Role Stimulant Substance abuse problem Systems Biology Testing Therapeutic Tissues Ursidae Family Viral Viral Proteins Viral reservoir Virus advanced system antiretroviral therapy chemokine clinically relevant comorbidity cytokine dopaminergic neuron drug of abuse druggable target experience experimental study gene regulatory network genetic manipulation improved in vivo induced pluripotent stem cell innovation macrophage member multidrug abuse neural circuit neuroAIDS neuroadaptation neuron loss neuroprotection novel novel therapeutics promoter public health relevance reactivation from latency response therapeutic target therapeutically effective transcriptomics

AIDS/HIV problem Alcohol abuse Alzheimer&apos s Disease Anti-Retroviral Agents Astrocytes Automobile Driving CRISPR/Cas technology Cells Cerebrum Closure by clamp Computing Methodologies Data Disease Disease Progression Dissection Drug Modelings Drug abuse Electrophysiology (science)Exposure to Gene Expression Gene Expression Profiling Gene Expression Regulation Genomic approach HIV HIV Envelope Protein gp120 Human Inflammation Injury Integration Host Factors Lead Light Literature Mediator of activation protein Methamphetamine Microglia Modeling Monitor Morphine Nerve Degeneration Neuraxis Neurodegenerative Disorders Neurons Neuropathogenesis Neuropsychology Opioid Organoids Pathogenesis Persons Pharmaceutical Preparations Preparation Property Proviruses Regulation Regulator Genes Role Stimulant Substance abuse problem Systems Biology Testing Therapeutic Tissues Ursidae Family Viral Viral Proteins Viral reservoir Virus advanced system antiretroviral therapy chemokine clinically relevant comorbidity cytokine dopaminergic neuron drug of abuse druggable target experience experimental study gene regulatory network genetic manipulation improved in vivo induced pluripotent stem cell innovation macrophage member multidrug abuse neural circuit neuroAIDS neuroadaptation neuron loss neuroprotection novel novel therapeutics promoter public health relevance reactivation from latency response therapeutic target therapeutically effective transcriptomics

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项目摘要

Summary HIV-infected microglia release cytokines, chemokines and viral gene products, such as gp120 and tat, that are toxic to neurons. In this proposal, we will use human induced pluripotent stem cells (iPSCs) to generate cortical and dopaminergic neurons as well as microglia, which will be cultured as organoids to model HIV-drug abuse interactions in conjunction with in-depth genomic approaches and electrophysiology. We show electrophysiological results that demonstrate that the levels of differentiation of the neurons in our organoids are comparable to in vivo and ex vivo preparations and are among the best that can be found in the scientific literature. To identify candidate host regulators of HIV expression and mediators of HIV-induced tissue damage and disease progression, we will expose microglia-containing cerebral organoids to methamphetamine (METH), a stimulant, and morphine, an opiate, which are members of two of the classes of drugs of abuse that are more prevalent among People Living with HIV/AIDS (PLWHA). Cerebral organoids will be exposed to toxic HIV products such as Tat, gp120, drugs of abuse and combination antiretroviral therapy (cART). In some experiments we will also incorporate iPSC-derived astrocytes into microglia-containing cerebral organoids to test the role of astrocytes in neuroprotection and neurodegeneration. We will carry out single-cell gene expression profiling of iPSC-derived organoids exposed to drugs of abuse, HIV products, and cART and we will employ an advanced systems biology strategy to generate testable mechanistic hypotheses on the pathogenesis of neurodegeneration and tissue damage in neuroHIV (Aim 1) and identify candidate regulators of the LTR promoter that may shed light on the regulation of latency and reactivation of the HIV provirus (Aim 2). In preliminary studies, this computational experimental approach allowed us to identify candidate drivers of gene expression changes associated with neuroHIV and neurodegenerative diseases, including Alzheimer’s disease and drug and alcohol abuse. These findings support the overarching hypothesis that dissection of the gene regulatory network of the central nervous system will pave the way for the identification of novel mechanistic hypotheses and druggable targets to improve neuropsychological functioning of PLWHA and substance abuse comorbidity.