Deciphering the single-nucleus genomic regulatory structure of opioid use disorder in the human brain

破译人脑阿片类药物使用障碍的单核基因组调控结构

• 批准号: 10729280
• 负责人: Janitza Liz Montalvo-Ortiz
• 金额: $ 50.25万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10729280
• 关键词: 3-Dimensional; Amygdaloid structure; Autopsy; Brain; Brain region; Cell Nucleus; Cells; Chromatin Structure; DNA; DNA Methylation; DNA Sequence Alteration; DNA methylation profiling; Data Collection; Data Set; Environment; Epidemic; Epigenetic Process; Etiology; Gene Expression Regulation; Genes; Genetic Research; Genome; Genomics; Goals; Human; Individual; Joints; Maps; Modification; Molecular; Molecular Target; Nucleus Accumbens; Peripheral; Pharmaceutical Preparations; Prefrontal Cortex; Prevention; Regulator Genes; Research; Role; Sampling; Signal Transduction; Structure; Tissues; United States; Untranslated RNA; Validation; Variant; Work; addiction; cell type; cohort; epigenomics; genetic risk factor; genetic variant; genome wide association study; genome-wide; hospitalization rates; innovation; insight; methylomics; multiple omics; novel; opioid use disorder; overdose death; programs; transcriptomics

Project Summary Opioid use disorder (OUD) has reached epidemic levels in the Unites States, associated with increased rates of hospitalization and drug overdose death, the latter showing a significant steep rise of up to 29.4% in 2020. While genetic risk factors have been identified in recent large-scale genome-wide association studies (GWAS) of OUD, these explain only part of the variance and often map to noncoding regions. Epigenetic modifications have been implicated in the etiology of opioid use disorders (OUD) underlying the gene and environment interplay. We and others have found that alterations of DNA methylation (5mC), one of the most studied epigenetic mechanisms, is associated with OUD in both human peripheral and postmortem brain. However, most of this work has been done in bulk tissues, which obscures the functional role of the cellular diversity in human cells. Further, research is needed to assess additional and novel epigenetic regulatory layers to gain a better understanding of its contribution to gene regulation and its ability to interpret the functionality of GWAS genetic variants in the context of OUD. Here, I offer a novel framework to tackle these gaps and challenges: 1) conduct a simultaneous profiling of DNA methylation, DNA hydroxymethylation, and 3D genome structure in single human nuclei, 2) identify OUD-dependent regulatory signatures within cell types and brain regions, 3) evaluate the crosstalk between the different epigenomic regulatory layers, and 4) construct gene programs to finely map OUD GWAS variants and polygenic signals to function. This comprehensive single-cell multiomics mapping of OUD will examine the dorsolateral prefrontal cortex (DLPFC), amygdala (BLA), and nucleus accumbens (NAcc), part of the addiction circuitry, of human postmortem brain samples collected from the UTHealth Brain Collection datasets and using the VA Brain Bank (NPBB) as a validation cohort. This work is highly innovative and will open new lines of research the genetics and epigenetics of OUD by providing novel mechanistic insights on its gene regulatory structure in the human brain. This proposed study will identify and help inform molecular targets to be used as prevention and treatment efforts for individuals suffering from OUD.

项目摘要 阿片类药物使用障碍（OUD）在美国已达到流行病的水平， 住院和药物过量死亡，后者在2020年大幅上升至29.4%。 虽然在最近的大规模全基因组关联研究（GWAS）中已经确定了遗传风险因素， 但是，这些基因只能解释部分变异，并且通常映射到非编码区。表观遗传修饰 与阿片类药物使用障碍（OUD）的病因学有关， 相互作用我们和其他人已经发现，DNA甲基化（5mC）的改变， 表观遗传机制与人类外周和死后脑中的OUD相关。然而，在这方面， 大部分的研究工作都是在大块组织中进行的，这使得细胞多样性的功能作用变得模糊不清， 人类细胞。此外，还需要进行研究，以评估额外的和新的表观遗传调控层， 更好地理解其对基因调控的贡献及其解释GWAS功能的能力 在OUD背景下的遗传变异。在这里，我提供了一个新的框架来解决这些差距和挑战：1） 进行DNA甲基化，DNA羟甲基化和3D基因组结构的同时分析， 单个人类核，2）识别细胞类型和脑区域内依赖OUD的调节信号，3） 评估不同表观基因组调控层之间的串扰，以及4）构建基因程序， 精细地映射OUD GWAS变体和多基因信号以发挥功能。这种全面的单细胞多组学 OUD的定位将检查背外侧前额叶皮层（DLPFC）、杏仁核（BLA）和核团 成瘾回路的一部分，人类死后的大脑样本收集自 UTHealth Brain Collection数据集，并使用VA Brain Bank（NPBB）作为验证队列。这项工作是 高度创新，将开辟新的研究路线的遗传学和表观遗传学的OUD提供新的 在人类大脑中的基因调控结构的机械见解。这项拟议的研究将确定和 帮助告知分子靶点，用于预防和治疗患有 OUD。