权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
10644020
负责人：
Christine Cheng
金额：
$ 152.72万
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/10644020
关键词：
3-Dimensional Acquired Immunodeficiency Syndrome Acute Alcohols Astrocytes Behavior Biological Assay Blood Blood - brain barrier anatomy Blood Vessels Brain Brain region Cell Nucleus Cells Central Nervous System 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 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 Substance Use Disorder Technology Transcript Validation Variant Vascularization Viral Load result Viral reservoir acute infection addiction antiretroviral therapy 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 immune cell infiltrate in vivo knock-down nano-string neurocognitive disorder neurotoxicity new technology novel overexpression resilience response seroconversion single nucleus RNA-sequencing stimulant use transcriptome transcriptomics

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.

项目总结