Single Cell Transcriptomics of the Cocaine Use Disorder in the Context of HIV

HIV 背景下可卡因使用障碍的单细胞转录组学

基本信息

批准号：
10454684
负责人：
Christine Cheng
金额：
$ 156.2万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-15 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10454684
关键词：
3-Dimensional Acquired Immunodeficiency Syndrome Acute Address Alcohols Astrocytes Behavior Biological Assay Blood Blood - brain barrier anatomy Blood Vessels Brain Brain region Cell Nucleus Cells Clinical Clustered Regularly Interspaced Short Palindromic Repeats Cocaine Cocaine Users Cocaine misuse Cocaine use disorder Computer Analysis Corpus striatum structure Data Set Databases Development Disease Dorsal Event Exhibits Gene Expression Genes HIV HIV Infections HIV-1 HIV-associated neurocognitive disorder Human Immune Immunosuppression In Vitro Incidence Individual Infection Inflammation Inflammatory Interneurons Knock-in Knock-out Lead Leptomeninges Methamphetamine Methods Microglia Microtubules Modeling Molecular Neuraxis Neurocognitive Neurocognitive Deficit Neuroglia Neurologic Neurologic Dysfunctions Neuronal Injury Neurons Organoids Pathogenesis Pathway interactions Patients Pattern Pericytes Persons Pharmaceutical Preparations Population Prefrontal Cortex Primary Infection Property Regulation Research Route Sampling Small Nuclear RNA Substance Use Disorder Technology Transcript Tumor-infiltrating immune cells Validation Variant Viral Load result Viral reservoir acute infection addiction antiretroviral therapy base blood-brain barrier disruption blood-brain barrier permeabilization brain cell cell type chronic inflammatory disease cocaine use gene regulatory network gene therapy genome-wide glial activation immune activation in vivo knock-down nano-string neurocognitive disorder neurotoxicity new technology novel overexpression resilience response seroconversion stimulant use transcriptome transcriptome sequencing transcriptomics

3-Dimensional Acquired Immunodeficiency Syndrome Acute Address Alcohols Astrocytes Behavior Biological Assay Blood Blood - brain barrier anatomy Blood Vessels Brain Brain region Cell Nucleus Cells Clinical Clustered Regularly Interspaced Short Palindromic Repeats Cocaine Cocaine Users Cocaine misuse Cocaine use disorder Computer Analysis Corpus striatum structure Data Set Databases Development Disease Dorsal Event Exhibits Gene Expression Genes HIV HIV Infections HIV-1 HIV-associated neurocognitive disorder Human Immune Immunosuppression In Vitro Incidence Individual Infection Inflammation Inflammatory Interneurons Knock-in Knock-out Lead Leptomeninges Methamphetamine Methods Microglia Microtubules Modeling Molecular Neuraxis Neurocognitive Neurocognitive Deficit Neuroglia Neurologic Neurologic Dysfunctions Neuronal Injury Neurons Organoids Pathogenesis Pathway interactions Patients Pattern Pericytes Persons Pharmaceutical Preparations Population Prefrontal Cortex Primary Infection Property Regulation Research Route Sampling Small Nuclear RNA Substance Use Disorder Technology Transcript Tumor-infiltrating immune cells Validation Variant Viral Load result Viral reservoir acute infection addiction antiretroviral therapy base blood-brain barrier disruption blood-brain barrier permeabilization brain cell cell type chronic inflammatory disease cocaine use gene regulatory network gene therapy genome-wide glial activation immune activation in vivo knock-down nano-string neurocognitive disorder neurotoxicity new technology novel overexpression resilience response seroconversion stimulant use transcriptome transcriptome sequencing transcriptomics

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项目摘要

PROJECT SUMMARY Systemic immune activation in people living with HIV has been hypothesized to account for higher incidence of chronic inflammatory diseases, including HIV-associated neurocognitive disorders (HAND). Acute HIV infection in the CNS is thought to initiate a cascade of pro-inflammatory events that result in inflammation-induced neuronal injury and associated neurocognitive disorders that are evident even in the present combination antiretroviral therapy (cART) era. The use of psychostimulants (such as cocaine and methamphetamine) and alcohol has been shown to disrupt BBB integrity. Disrupted BBB may increase immune cell infiltrating into the CNS and promote glial activation, increased inflammation and neurotoxicity. Interestingly, increased permeability of BBB has been implicated in the progression of HIV neurological dysfunction. Thus, the combined effect of cocaine usage and HIV infection can cause an additive effect on BBB disruption and further impact HIV-related neurocognitive impairments. However, not much genome-wide molecular level study has been done in understanding BBB integrity in substance use disorder and in HIV infection/HAND. The proposed study will address this important question. Our central hypothesis is that cocaine misuse exacerbates HIV pathogenesis in the CNS by disrupting blood-brain barrier and dysregulating the glial population in the brain. Our overall objective is to exploit cell type specific transcriptomic information at the single nuclei level from patient brain samples to characterize the effects of cocaine use disorder on CNS neuronal and glial cells, HIV infection and HANDs. We will characterize single nuclei gene expression and identify dysregulated gene regulatory networks in each of the neuronal and glial populations associated with cocaine misuse in HIV infected individuals and/or with HANDs. We will also perform computational analysis to identify neuronal and glial cell regulatory networks altered by cocaine misuse. In the validation and functional characterization component, we will characterize top genes in 3D brain organoid model and will characterize with CRISPR knockout and overexpression of the gene. Successful completion of these aims will have significant research and clinical impact by 1) elucidating how cocaine misuse alters HIV/HAND pathogenesis in the CNS, and 2) discovering candidate molecules to regulate HIV infection or persistence in the CNS in the context of cocaine misuse.

项目摘要假设艾滋病毒患者的全身免疫激活慢性炎症性疾病，包括与HIV相关的神经认知疾病（手）。急性HIV感染中枢神经系统被认为会引发一系列促炎事件，导致炎症引起的即使在目前的组合中，神经元损伤和相关的神经认知疾病也很明显抗逆转录病毒疗法（购物车）时代。使用心理刺激剂（例如可卡因和甲基苯丙胺）和酒精已被证明会破坏BBB的完整性。破坏的BBB可能会增加免疫细胞，从而渗入中枢神经系统并促进神经胶质激活，炎症和神经毒性增加。有趣的是，渗透率提高 BBB的含义与HIV神经功能障碍的进展有关。因此，可卡因的使用和HIV感染会对BBB的破坏产生累加作用，并进一步影响HIV相关神经认知障碍。但是，在全基因组分子水平研究中没有进行太多了解药物使用障碍和HIV感染/手的BBB完整性。拟议的研究将解决这个重要的问题。我们的中心假设是可卡因滥用加剧了HIV发病机理在中枢神经系统中，通过破坏血脑屏障和大脑中的神经胶质种群的失调。我们的整体目的是从患者脑中利用单个核水平的细胞类型特定的转录组信息样品表征可卡因使用障碍对中枢神经系统神经元和神经胶质细胞的影响，HIV感染和手。我们将表征单核基因表达并确定基因调节网络失调在每个与可卡因有关的神经元和神经胶质种群中，在艾滋病毒感染的个体和/或用手。我们还将执行计算分析以识别神经元和神经胶质细胞调节网络因可卡因滥用而改变。在验证和功能表征组件中，我们将表征顶部 3D脑器官模型中的基因，并将以CRISPR敲除和基因过表达为特征。这些目标的成功完成将对1）阐明如何产生重大的研究和临床影响滥用可卡因会改变中枢神经系统中的艾滋病毒/手发病，2）发现候选分子以调节在可卡因滥用的背景下，中枢神经系统中的艾滋病毒感染或持久性。