Integrating primate-rodent cell types and epigenomics to identify conservation in substance addiction

整合灵长类-啮齿类细胞类型和表观基因组学来识别物质成瘾的保守性

• 批准号: 10543174
• 负责人: BaDoi Nguyen Phan
• 金额: $ 5.27万
• 依托单位: CARNEGIE-MELLON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-05 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10543174
• 关键词: Affect; Alcohol consumption; Alcohols; Animals; Area; Atlases; Automobile Driving; Autopsy; Behavior; Biological Assay; Brain; Brain region; Cannabis; Cell Nucleus; Cells; Chromatin; Clinical; Clinical Research; Collaborations; Communities; Comparative Genomic Analysis; Complex; Corpus striatum structure; Data; Development; Dopamine D1 Receptor; Dorsal; Drug Addiction; Enhancers; Epigenetic Process; Fellowship; Foundations; Future; Gene Expression Profile; Genes; Genetic; Genetic Variation; Genome; Heritability; Human; Human Genetics; Individual; Letters; Link; Macaca; Machine Learning; Maps; Medicine; Mentors; Modeling; Molecular; Monkeys; Mus; Neurons; Nicotine; Nucleus Accumbens; Persons; Pharmaceutical Preparations; Phenotype; Physicians; Predisposition; Primates; Quantitative Trait Loci; Rattus; Research; Research Training; Resolution; Rewards; Risk; Risk Behaviors; Rodent; Rodent Model; Scientist; Specificity; Speed; Substance Addiction; Substance Use Disorder; System; Testing; Training; Transposase; Variant; Work; addiction; base; brain cell; brain tissue; cell type; comparative genomics; epigenomics; experience; experimental study; genetic makeup; genome wide association study; genomic data; human disease; insight; interest; leadership development; machine learning algorithm; mammalian genome; model organism; mouse genetics; neural circuit; neurobehavioral; neuropsychiatry; nonhuman primate; novel; personalized medicine; pre-clinical research; prevent; programs; risk variant; single nucleus RNA-sequencing; skills; substance use; trait; transcriptomics

Project Summary/Abstract Substance use disorders (SUD) of many highly addictive drugs affect more than 100 million people worldwide. Genetic variations associated with complex neuro-behavioral traits, such as drug addiction, are likely to impact enhancers which have a high degree of cell type-specificity and can be conserved across species. Furthermore, variation in addiction behavior has been linked to genetic variation in both human and rodents. Thus, it follows that genetic mechanisms driving addiction behavior, specifically at cell type-specific enhancers, might also be conserved between primates and rodents. I hypothesize that risk variants for some SUDs may lie in enhancers of distinct cell types in the reward areas and not others, providing insight into the cell types that are critical to SUDs. This project proposes to identify the gene markers and putative enhancers of cell types that are conserved or clade-specific to primates and rodents and of these, which are enriched for SUD human genetic risk variants. The proposal comprises of the following aims: Aim 1: identify the primate-rodent conserved cell types and marker gene profiles enriched for human SUD risk variants. Aim 2: identify the primate-rodent conserved putative enhancer profiles to test whether mouse substance use behavior risk loci disrupt similar putative conserved enhancers to human SUD risk loci. Together, these experiments could reveal primate-rodent gene and enhancer atlas of conserved and species-specific cell types of the reward system by integrating single-nuclei genomics data across multiple mammalian species. This information is critically important because better understanding of how an individual’s genetic makeup could affect the cells of the reward circuit will inform future work to craft personalized, targeted SUD therapy. Thus, this work integrates closely with my clinical interests in addiction medicine. This proposal outlines a combination of rigorous mentored research training, longitudinal clinical experiences, coursework, and professional and leadership development activities. The intellectual, technical, and professional skills refined during this fellowship training period will be instrumental in my development as an aspiring physician scientist in the clinical field of addiction medicine.

项目摘要/摘要 许多高度成瘾药物的物质使用障碍(SUD)影响着全球超过1亿人。 与复杂的神经行为特征相关的遗传变异，如吸毒成瘾，可能会影响 增强剂具有高度的细胞类型特异性，可以跨物种保存。此外， 成瘾行为的变化与人类和啮齿动物的遗传差异有关。因此，它是这样的 驱动成瘾行为的遗传机制，特别是在细胞类型特定的增强子上，也可能是 在灵长类和啮齿动物之间保存。我推测某些肥皂水的风险变种可能存在于增强剂中。 奖赏区域中不同的细胞类型，而不是其他区域，提供对以下方面至关重要的细胞类型的洞察 肥皂水。该项目建议确定保守的细胞类型的基因标记和假定的增强子。 或者是灵长类和啮齿动物特有的分支，以及这些富含SUD人类遗传风险变异的基因。 该方案包括以下目标：目标1：确定灵长类啮齿动物保守的细胞类型和标记 富含人类sud风险变异的基因图谱。目标2：鉴定保守的灵长类-啮齿动物 测试小鼠物质使用行为风险基因座是否干扰相似假定保守的增强子谱 人类SUD风险基因的增强剂。总之，这些实验可以揭示灵长类啮齿动物的基因和增强子。 整合单核基因组学的奖赏系统保守和物种特异性细胞类型图谱 多个哺乳动物物种的数据。这一信息至关重要，因为更好地理解 个体的基因构成如何影响奖励回路的细胞，这将为未来的工作提供信息 个性化的、有针对性的苏打疗法。因此，这项工作与我在成瘾方面的临床兴趣密切相关。 医药。这份提案概述了严格的指导研究培训、纵向临床 经验、课程安排，以及专业和领导力发展活动。知识分子，技术人员， 在这次团契培训期间精炼的专业技能将有助于我作为一名 在成瘾医学临床领域有抱负的内科科学家。