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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：
10398922
负责人：
Christine Cheng
金额：
$ 68.96万
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/10398922
关键词：
3-Dimensional Acquired Immunodeficiency Syndrome Astrocytes Autologous Autopsy Biological Models Brain CCL2 gene CXCL10 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 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 Lead Link Malignant Neoplasms Microglia Molecular Morphine Myeloid Cells Nerve Degeneration Neurocognitive Neuroglia Neurologic Dysfunctions Neuronal Injury Neurons Neuropathogenesis Nuclear Export Opiate Addiction Opioid Organoids Osteoporosis Pathway interactions Patients Peripheral Blood Mononuclear Cell Persons Pharmaceutical Preparations Population Predisposition Production Publishing RNA Risk Signal Transduction Surveys Testing Tissues Toxic effect Viral Viral Proteins Viremia Virus Virus Diseases antiretroviral therapy base 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 macrophage mitochondrial dysfunction monocyte mu opioid receptors neuroinflammation neurotoxicity opioid abuse opioid exposure opioid injection opioid use opioid use disorder overdose death pathogen peripheral blood prevent response single-cell RNA sequencing socioeconomics substance use 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.

摘要