Single Cell Transcriptomic and Epigenomic Dissection of Opioid and Cocaine Responses in HIV

HIV 中阿片类药物和可卡因反应的单细胞转录组和表观基因组解析

• 批准号: 10220620
• 负责人: Myriam Heiman
• 金额: $ 246.19万
• 依托单位: BROAD INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10220620
• 关键词: AIDS/HIV problem; ATAC-seq; Addictive Behavior; Address; Affect; Amygdaloid structure; Animal Model; Animals; Atlases; Biological; Biological Assay; Biology; Brain; Brain region; Cell physiology; Cells; Characteristics; Chronic; Cocaine; Corpus striatum structure; Country; DNA; Data; Data Set; Dementia; Development; Disease; Disease Management; Dissection; Dorsal; Enhancers; Epigenetic Process; Event; Exposure to; Future; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Transcription; Genomics; HIV; HIV Infections; HIV-associated neurocognitive disorder; Hippocampus (Brain); Human; In Situ Hybridization; Individual; Infection; Insula of Reil; Knowledge; Link; M cell; Maps; Mediation; Molecular; Mus; National NeuroAids Tissue Consortium; Neurobiology; Neurocognitive Deficit; Neuronal Injury; Nucleic Acid Regulatory Sequences; Nucleus Accumbens; Opioid; Pathway interactions; Patients; Pharmacology; Phenotype; Predisposition; Prefrontal Cortex; Process; Property; Proteins; RNA; Regulator Genes; Resolution; Resources; Sampling; Self Administration; Specificity; Substance Addiction; Substance Use Disorder; Untranslated RNA; Validation; Variant; Ventral Tegmental Area; Viral Load result; Withdrawal Symptom; addiction; antiretroviral therapy; base; cell type; chronic infection; cocaine self-administration; cocaine use; cohort; disorder control; epigenomics; experience; genetic signature; genome-wide; human tissue; immune function; in vivo; in vivo Model; mortality; mouse model; nervous system disorder; neuroinflammation; new therapeutic target; novel therapeutics; opioid use; response; single-cell RNA sequencing; substance use; therapeutic target; trait; transcriptome; transcriptomics

Abstract Substance use disorder (SUD) is a common and debilitating condition characterized by compulsive use of an addictive substance, inability to control the use of this substance, and the emergence of withdrawal symptoms in the absence of the substance. Despite great advances in our understanding of changes that occur in various brain regions in the context of addiction/SUD, there is a limited understanding of the diversity of cell types and gene expression profiles of cells within these human brain regions, and how exposures to addictive substances such as opioids and cocaine influence the molecular properties and functions of these cells. Over 50% of HIV- infected patients experience neurological disorders collectively termed HIV-Associated Neurocognitive Disorders (HAND), which ranges from the asymptomatic neurocognitive impairment to severely disabling dementia. The use of addictive substances by HIV-infected individuals has been linked to diminished immune function, increased neuroinflammation and neuronal injury, and exacerbation of HAND. Here, we seek to directly dissect the common and distinct molecular bases of SUD/HIV infection/HAND effects on distinct cell types by systematic profiling, dissection, computational integration, and experimental validation of their transcriptional, epigenomic, and genetic signatures across individuals, brain regions, and cell types. Aim 1: We use genetic, epigenomic, and transcriptional profiles, generating a total of ~28 million genome-wide maps at the single-cell (sc) level using 2,800 samples with 10,000 cells per sample; these span 7 brain regions (prefrontal cortex, nucleus accumbens, ventral tegmental area, dorsal striatum, insula, amygdala, hippocampus), two assays (scRNA, scATAC), four phenotypic groups (SUD+/HIV+, SUD+/HIV-, SUD-/HIV+, SUD-/HIV-), and a total of 200 subjects (50 in each phenotypic group). Aim 2: We integrate these datasets to predict driver genes, regulatory regions, variants, and pathways, and the cell types and brain regions where they act. Aim 3: We validate high-priority findings at the molecular level, and functionally validate the highest priority targets’ ability to modulate addictive behaviors in mouse models of in vivo cocaine self-administration. The resulting datasets will help guide the search for new therapeutics, by providing detailed therapeutic targets, and the specific conditions where they are predicted to act.

抽象的 物质使用障碍 (SUD) 是一种常见且令人衰弱的疾病，其特征是强迫性使用某种物质 成瘾物质、无法控制该物质的使用以及出现戒断症状 在没有该物质的情况下。尽管我们对各种变化的理解取得了很大进步 在成瘾/SUD 的背景下，人们对大脑区域的细胞类型和多样性的了解有限。 这些人脑区域内细胞的基因表达谱，以及如何接触成瘾物质 阿片类药物和可卡因等会影响这些细胞的分子特性和功能。超过 50% 的艾滋病毒 - 感染患者会出现神经系统疾病，统称为艾滋病毒相关神经认知障碍 疾病 (HAND)，范围从无症状的神经认知障碍到严重残疾 失智。 HIV 感染者使用成瘾物质与免疫力下降有关 功能、神经炎症和神经元损伤增加以及 HAND 恶化。在这里，我们寻求 直接剖析 SUD/HIV 感染/HAND 对不同细胞的影响的共同和不同的分子基础 通过系统分析、解剖、计算集成和实验验证来确定类型 跨个体、大脑区域和细胞类型的转录、表观基因组和遗传特征。目标一：我们 使用遗传、表观基因组和转录图谱，生成总共约 2800 万个全基因组图谱 单细胞 (sc) 水平使用 2,800 个样本，每个样本包含 10,000 个细胞；这些跨越 7 个大脑区域 （前额皮质、伏隔核、腹侧被盖区、背侧纹状体、岛叶、杏仁核、 海马），两种检测（scRNA，scATAC），四种表型组（SUD+/HIV+，SUD+/HIV-，SUD-/HIV+， SUD-/HIV-），总共 200 名受试者（每个表型组 50 名）。目标 2：我们将这些数据集集成到 预测驱动基因、调控区域、变异和通路，以及细胞类型和大脑区域 他们行动了。目标 3：我们在分子水平上验证高优先级的发现，并在功能上验证最高优先级的发现 优先目标在体内可卡因自我给药小鼠模型中调节成瘾行为的能力。 由此产生的数据集将通过提供详细的治疗方法来帮助指导新疗法的搜索 目标，以及预测它们采取行动的具体条件。