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Single cell determinants of brain in the context of viral persistence in SIV/cART/cocaine non-human primates

SIV/cART/可卡因非人灵长类动物病毒持续存在时大脑的单细胞决定因素

基本信息

批准号：
10683001
负责人：
Shilpa J. Buch
金额：
$ 249.41万
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：
2023
资助国家：
美国
起止时间：
2023-06-01 至 2028-02-29
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10683001
关键词：
Affect Agreement Anatomy Animal Model Animals Area Atlases BRAIN initiative Biological Assay Brain Brain region Cell Culture Techniques Cell Separation Cells Cellular Assay Censuses Central Nervous System Chromatin Cocaine Controlled Study Corpus striatum structure DNA Data Data Analyses Disease Drug abuse Environment Epigenetic Process Future Gene Expression Gene Expression Regulation Generations Genes Genetic Transcription Glass HIV HIV Infections Hippocampus Human Immune Impaired cognition Impairment Infection Macaca mulatta Macrophage Mediating Methods Microglia Modeling Modification Molecular Monkeys Morphine Mus Myelogenous National Institute of Drug Abuse Neuropathogenesis Opioid Pathogenicity Persons Pharmaceutical Preparations Phenotype Prefrontal Cortex Primates Process RNA Reporting Research Personnel Role SIV Specific qualifier value Tissues Transposase United States National Institutes of Health Validation Viral Viral reservoir Virus Diseases Work brain cell brain dysfunction cell type cocaine exposure cocaine use cognitive function combinatorial data resource drug of abuse epigenetic regulation epigenome high risk immune function innovation insight member multidisciplinary nonhuman primate novel programs response single cell sequencing single-cell RNA sequencing transcriptome transcriptomic profiling transcriptomics

项目摘要

PROJECT SUMMARY Drug abuse and HIV infection co-exist and are difficult to study due to challenges in people living with HIV (PLWH) who abuse drugs. One of the prime areas of pathogenic interactions of HIV and drugs of abuse is the brain, which carries additional study limitations. To obtain rigorous data on the effects of HIV and cocaine on the brain, we will utilize well-studied nonhuman primate animal model, Simian immunodeficiency virus (SIV)- infected and uninfected control rhesus monkeys, in the presence or absence of cocaine. Single cell sequencing assays enable cell type-specific analysis of the role of specific cell types in both healthy brain function and disease. The overall objective of this proposal by multidisciplinary team of investigators is to reveal the single cell determinants of brain in the context of viral persistence in SIV/cART/cocaine non-human primates. Simultaneous single-cell RNA sequencing and single-cell Assay for Transposase- Accessible Chromatin sequencing (scMultiome-seq) will be carried out on cells isolated from the prefrontal cortex (PFC), striatum, and hippocampus from each animal. Data will be processed and analyzed to derive cell type-specific regulatory programs and changes in these programs that regulate neuropathogenesis in the primate brains. These studies will provide unique and valuable insights into SIV/cocaine/cART interactions in the brain while also providing crucial experimental validation of the findings in humans. Successful completion of these innovative single-cell studies and data analyses methods will generate a single cell transcriptome and epigenome atlas of cellular part list for three NIDA-relevant brain regions, PFC, striatum, and hippocampus. These results will illuminate novel insights into transcriptomic and epigenetic landscapes of CNS and how they are altered by HIV and cocaine use.

项目总结药物滥用和艾滋病毒感染并存，由于艾滋病毒携带者面临的挑战，很难进行研究 (PLWH)滥用药物者。艾滋病毒和滥用药物致病相互作用的主要领域之一是大脑，这带来了额外的研究限制。要获得有关艾滋病毒和可卡因对人类健康影响的严格数据大脑，我们将利用研究得很好的非人类灵长类动物模型，猿猴免疫缺陷病毒(SIV)- 感染和未感染对照恒河猴，在可卡因存在或不存在的情况下。单细胞测序分析能够对特定细胞类型在两个健康大脑中的作用进行特定类型的分析功能和疾病。这项由多学科调查组提出的建议的总体目标是揭示在SIV/CART/可卡因非人类中病毒持续背景下脑部的单细胞决定因素灵长类动物。转座酶可及性的单细胞RNA测序和单细胞检测染色质测序(scMultiome-seq)将在从前额叶皮质(PFC)分离的细胞上进行，每种动物的纹状体和海马体。将对数据进行处理和分析，以得出特定于单元格类型的数据调节程序和这些调节灵长类大脑中神经发病机制的程序的变化。这些研究将为SIV/可卡因/CART在大脑中的相互作用提供独特和有价值的见解这也为这些发现在人类身上提供了关键的实验验证。成功完成这些任务创新的单细胞研究和数据分析方法将产生单细胞转录组和与NIDA相关的三个脑区，前额叶、纹状体和海马区的表观基因组图谱。这些结果将阐明对中枢神经系统转录和表观遗传景观的新见解以及如何它们会因艾滋病毒和可卡因的使用而改变。