Synergistic Mechanisms of chronic Innate Immune Activation in Microglia by Opiates and HIV Infection

阿片类药物和 HIV 感染对小胶质细胞慢性先天免疫激活的协同机制

基本信息

批准号：
10613922
负责人：
Christine Cheng
金额：
$ 67.7万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-15 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10613922
关键词：
3-Dimensional Acquired Immunodeficiency Syndrome Astrocytes Autologous Autopsy Binding Biological Models Brain CCL2 gene CXCL10 gene CXCR3 gene Cardiovascular Diseases Cell Communication Cell Culture Techniques Cell Line Cell Nucleus Cells Cellular Metabolic Process Chronic Clustered Regularly Interspaced Short Palindromic Repeats Development Exposure to Functional disorder Future Genetic Transcription Gliosis HIV HIV Infections HIV antiretroviral HIV-1 HIV-associated neurocognitive disorder Human Immune Immune System Diseases Incidence Individual Infection Inflammation Inflammatory Inflammatory Response Innate Immune Response Interferons Interruption Intervention Introns Knock-out Link Macrophage Malignant Neoplasms Microglia Molecular Morphine Myeloid Cells Nerve Degeneration Neurocognitive Neuroglia Neurologic Dysfunctions Neuronal Injury Neurons Neuropathogenesis Nuclear Export Opiate Addiction Opioid Opioid Receptor Organoids Osteoporosis Pathway interactions Patients Peripheral Blood Mononuclear Cell Persons Pharmaceutical Preparations Population Predisposition Production Productivity Publishing RNA Risk Signal Transduction Surveys Testing Tissues Toxic effect Viral Viral Proteins Viremia Virus Virus Diseases antiretroviral therapy cell injury cell type chronic inflammatory disease comorbidity cytokine experience immune activation in vitro Model in vivo induced pluripotent stem cell inflammatory marker injection drug use innate immune sensing mitochondrial dysfunction monocyte neuroinflammation neurotoxicity opioid abuse opioid exposure opioid use opioid use disorder overdose death pathogen peripheral blood prevent response single-cell RNA sequencing socioeconomics substance use synergism therapeutic development transcriptomics viral DNA

项目摘要

ABSTRACT Persistent immune activation is the defining feature of HIV-1 infection in vivo and a driver of progression to end- stage AIDS. 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). Importantly, numerous studies have demonstrated that populations living with opioid-use disorder (OUD) have a higher occurrence of comorbid HIV infection, suggesting both potential socio-economic and neurocognitive influence. This comorbidity of OUD and HIV has also been shown to increase neuroinflammation and exacerbate the progression of HIV infection and HAND. While some studies have investigated the interactive effects of OUD and HAND in few cell types in isolation, the molecular mechanisms linking the two conditions is still largely unknown, especially in primary human microglia, neurons and astrocytes. Hence, we believe that this proposal fulfills a critical unmet need by establishing primary human neuronal cell cultures and an unbiased, systematic single cell transcriptomic survey of these cultures in the context of co-exposure of opiates and HIV-1 infection. In this proposal, we will establish 3D spheroid cultures consisting of induced pluripotent stem cell (iPSC)-derived human microglia, astrocytes and neurons, derived from 10 independent donor lines established at BUMC, that will recapitulate spatial complexity of cell-to-cell interactions in the brain, and interrogate the effect of HIV infection and morphine exposure on persistent innate immune activation. We will utilize cutting-edge single cell transcriptomics analysis to identify the microglia-intrinsic pathway that promotes induction of pro-inflammatory responses upon co-exposure to HIV and opiates and the neurodegenerative pathways contributing to neuronal cell injury. Finally, information from these transcriptomic studies will be leveraged to inform CRISPR/Cas-based knock-out strategies to selectively delete key pathways in iPSC-microglia to alleviate neuroinflammation. We believe that results from these studies will inform future therapeutic development to prevent HIV and opiate- induced neuroinflammation and prevent development of HAND in HIV+ substance use population.

抽象的持续的免疫激活是体内 HIV-1 感染的决定性特征，也是进展至终末期的驱动因素。艾滋病阶段。据推测，艾滋病毒感染者的全身免疫激活是导致较高感染率的原因。慢性炎症性疾病的发病率，包括艾滋病毒相关的神经认知障碍（HAND）。重要的是，大量研究表明，患有阿片类药物使用障碍 (OUD) 的人群 HIV 感染合并症的发生率较高，表明潜在的社会经济和神经认知影响。 OUD 和 HIV 的这种合并症也被证明会增加神经炎症并加剧 HIV 感染和 HAND 的进展。虽然一些研究调查了 OUD 的交互作用和 HAND 在少数细胞类型中单独存在，但连接这两种情况的分子机制仍然很大程度上是未知的。未知，特别是在原代人类小胶质细胞、神经元和星形胶质细胞中。因此，我们认为这项提议通过建立原代人类神经元细胞培养物和公正、系统的方法来满足关键的未满足需求在同时暴露阿片类药物和 HIV-1 感染的情况下对这些培养物进行单细胞转录组学调查。在本提案中，我们将建立由诱导多能干细胞 (iPSC) 衍生的 3D 球体培养物人类小胶质细胞、星形胶质细胞和神经元，源自 BUMC 建立的 10 个独立供体系，将重现大脑中细胞间相互作用的空间复杂性，并质疑艾滋病毒的影响感染和吗啡暴露对持续先天免疫激活的影响。我们将利用最先进的单细胞转录组学分析以确定促进促炎诱导的小胶质细胞内在途径共同暴露于艾滋病毒和阿片类药物的反应以及导致神经元退化的神经退行性途径细胞损伤。最后，这些转录组学研究的信息将被用于为基于 CRISPR/Cas 的研究提供信息敲除策略选择性地删除 iPSC-小胶质细胞中的关键通路以减轻神经炎症。我们相信这些研究的结果将为未来预防艾滋病毒和阿片类药物的治疗开发提供信息在 HIV + 物质使用人群中诱导神经炎症并预防 HAND 的发展。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

ATAC-seq Assay with Low Mitochondrial DNA Contamination from Primary Human CD4+ T Lymphocytes.

原代人 CD4 T 淋巴细胞低线粒体 DNA 污染的 ATAC-seq 测定。

DOI：
10.3791/59120
发表时间：
2019-03-22
期刊：
Journal of visualized experiments : JoVE
影响因子：
0
作者：
H. Rickner;Sheng;Christine S Cheng
通讯作者：
Christine S Cheng

Single cell transcriptomic profiling of a neuron-astrocyte assembloid tauopathy model.

神经元星形胶质细胞组合 tau 蛋白病模型的单细胞转录组分析。

DOI：
发表时间：
2022-10-21
期刊：
影响因子：
16.6
作者：
Rickner, Hannah Drew;Jiang, Lulu;Hong, Rui;O'Neill, Nicholas K;Mojica, Chromewell A;Snyder, Benjamin J;Zhang, Lushuang;Shaw, Dipan;Medalla, Maria;Wolozin, Benjamin;Cheng, Christine S
通讯作者：
Cheng, Christine S

Single cell transcriptomics reveals opioid usage evokes widespread suppression of antiviral gene program.

单细胞转录组学揭示阿片类药物的使用会引起抗病毒基因程序的广泛抑制。

DOI：
发表时间：
2020
期刊：
影响因子：
16.6
作者：
Karagiannis, Tanya T;Cleary Jr, John P;Gok, Busra;Henderson, Andrew J;Martin, Nicholas G;Yajima, Masanao;Nelson, Elliot C;Cheng, Christine S
通讯作者：
Cheng, Christine S

Human Pluripotent Stem Cell-Derived Intestinal Organoids Model SARS-CoV-2 Infection Revealing a Common Epithelial Inflammatory Response.

人类多能干细胞衍生的肠道类器官模型 SARS-CoV-2 感染揭示了常见的上皮炎症反应。

DOI：
发表时间：
2021-04-13
期刊：
影响因子：
5.9
作者：
Mithal, Aditya;Hume, Adam J;Lindstrom;Villacorta;Olejnik, Judith;Bullitt, Esther;Hinds, Anne;Mühlberger, Elke;Mostoslavsky, Gustavo
通讯作者：
Mostoslavsky, Gustavo