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M-SCORCH: Methamphetamine use disorder data generation center for Single Cell Opioid Responses in the Context of HIV

M-SCORCH：艾滋病毒背景下单细胞阿片类药物反应的甲基苯丙胺使用障碍数据生成中心

基本信息

批准号：
10404681
负责人：
Ya-Chi Ho
金额：
$ 190.59万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-15 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10404681
关键词：
ATAC-seq Address Amygdaloid structure Atlases Autopsy Basic Science Biological Biological Assay Biological Models Biological Process Biology Brain Brain region Candidate Disease Gene Cell Nucleus Cells ChIP-seq Characteristics Chromatin Clinical Sciences Collaborations Communities Complement Complex Confounding Factors (Epidemiology)Data Data Analyses Data Set Detection Disease Drug abuse Ensure Etiology Fluorescent in Situ Hybridization Functional disorder Ganglia Gene Expression Gene Expression Regulation Generations Genes Genomics Genotype HIV HIV Infections HIV-associated neurocognitive disorder Human Immune System Diseases Immunohistochemistry Impaired cognition Impairment Individual Injections Lead Medial Methamphetamine Methamphetamine use disorder Molecular Molecular Profiling Multiomic Data Neuraxis Neurobiology Neurocognition Neurosciences Nuclear Nuclear RNA Opioid Organoids Outcome Pathway interactions Patients Population Prefrontal Cortex Process Protocols documentation Public Health RNA Recording of previous events Research Research Personnel Resolution Resources Risk Route Sampling Science Small Nuclear RNA Specific qualifier value Symptoms Techniques Time Tissues Transcript Transposase Validation Ventral Striatum XCL1 gene addiction adverse outcome analysis pipeline brain cell brain tissue cell type cognitive function comorbidity data analysis pipeline data centers data quality data sharing data standards epigenetic regulation experimental study gene regulatory network global health high risk population immune function in vivo induced pluripotent stem cell insight methamphetamine use methamphetamine user nervous system disorder neurogenomics novel response syndemic tool transcriptome transcriptome sequencing transmission process viral RNA

项目摘要

PROJECT SUMMARY HIV and methamphetamine (MA) use are global health problems with devastating human and societal consequences. HIV and methamphetamine use also produce independent and additive impairments in neurocognition, and current clinical and basic science research suggest complex and currently inadequately understood interactions between HIV and MA pathophysiologies. We therefore propose to conduct comprehensive characterization, at the single cell/nuclear level, of human brain tissue and regionally specified organoids derived from human induced pluripotent stem cells. For these single nuclear (sn)RNA-seq and snATAC-seq analyses, we will sample 3 brain regions (prefrontal cortex, ventral striatum, and basolateral amygdala) critical for the neurobiological response to MA use in 20 brains from each of two donor groups, HIV+MA+ and HIV-MA+. These data generation efforts will complement ongoing efforts in these same brain regions from HIV-MA- and HIV+MA- donors and allow us to elucidate differences in gene expression and key biological pathways that occur in response to MA use, HIV, or the combination of the two. In addition, we will assay brain cell types for HIV transcripts, allowing us to identify cellular reservoirs of HIV in donor brains. These efforts will be aided by the use of human cortical organoid and medial ganglionic eminence organoid cultures, which offer complex, region-matched model systems recapitulating in vivo-like cellular diversity and microenvironments without potentially confounding factors including patient history, varying co-morbidities, prolonged postmortem intervals, or tissue degradation. We will then apply cutting edge and novel data analysis pipelines to integrate snRNA-seq and snATAC-seq data and identify cell population and gene expression differences between cell clusters (i.e., putative cell types) in different conditions. These data will also be integrated with external datasets from the SCORCH Consortium and other multi-omic data including genotype, RNA-seq, HiC, ChIP-seq, and ATAC-seq data from both healthy subjects and subjects with HIV infection, neurological disease, or a history of drug abuse. Finally, we will use multiplexed immunohistochemistry and single molecular fluorescent in situ hybridization to validate the cell type specific expression and co-expression of candidate genes, biological processes, and gene regulatory networks implicated in the etiology of HIV or MA pathophysiology. All data generation protocols and data analysis tools will be made freely available to the research community, and all data generated will be provided as both raw and processed resources. Taken together, the proposed experiments will generate invaluable resources and offer new biological insights into the human brain and its disorders.

项目总结