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: 10369613
• 负责人: BaDoi Nguyen Phan
• 金额: $ 5.18万
• 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 2025-11-04
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10369613
• 关键词: Affect; Alcohols; Animal Model; Animals; Area; Atlases; Automobile Driving; Autopsy; Behavior; Biological Assay; Brain; Brain region; 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; Lead; 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; Small Nuclear RNA; 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; mouse genetics; neural circuit; neurobehavioral; neuropsychiatry; nonhuman primate; novel; personalized medicine; pre-clinical research; prevent; programs; risk variant; skills; substance use; trait; transcriptome sequencing; 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.

项目总结/摘要 许多高度成瘾药物的物质使用障碍影响着全世界1亿多人。 与复杂的神经行为特征相关的遗传变异，如药物成瘾，可能会影响 增强子，其具有高度的细胞类型特异性并且可以在物种间保守。此外，委员会认为， 成瘾行为的变异与人类和啮齿动物的遗传变异有关。因此， 驱动成瘾行为的遗传机制，特别是细胞类型特异性增强子，也可能是 在灵长类和啮齿类动物中是保守的。我假设某些SUD的风险变异可能存在于增强子中， 不同的细胞类型在奖励区，而不是其他，提供洞察细胞类型是至关重要的， SUD。本计画提出要找出基因标记和假定的增强子的细胞类型是保守的 或对灵长类和啮齿类具有进化枝特异性，并且这些进化枝富含SUD人类遗传风险变体。 本研究的主要目的是：目的1：确定灵长类-啮齿类动物保守的细胞类型和标记 人类SUD风险变体的基因图谱。目的2：鉴定灵长类-啮齿类保守的假定基因 增强子谱，以测试小鼠物质使用行为风险基因座是否破坏类似的推定保守基因， 人SUD风险基因座的增强子。总之，这些实验可以揭示灵长类-啮齿动物基因和增强子 通过整合单核基因组学的奖励系统的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。这些信息至关重要，因为更好地了解 一个人的基因构成如何影响奖赏回路的细胞，这将为未来的工作提供信息。 个性化的、有针对性的SUD治疗。因此，这项工作与我对成瘾的临床兴趣紧密结合在一起。 药该提案概述了严格的指导研究培训，纵向临床 经验，课程，以及专业和领导力发展活动。智力，技术， 在奖学金培训期间磨练的专业技能将对我作为一名 成瘾医学临床领域有抱负的医生科学家。