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 许多高度添加剂的药物使用障碍（SUD）影响了全球超过1亿人。 与复杂的神经行为性状相关的遗传变异，例如药物成瘾，可能会影响 具有高度细胞类型特异性并且可以在物种上配置的增强剂。此外， 成瘾行为的变化与人和啮齿动物的遗传变异有关。那就跟随了 驱动成瘾行为的遗传机制，特别是在细胞类型特异性增强子上，也可能是 素数和啮齿动物之间的保守。我假设某些SUD的风险变异可能在于增强剂 奖励区域中不同的细胞类型，而不是其他细胞类型，提供对细胞类型的见解 泡沫。该项目的提案旨在识别保守的细胞类型的基因标记和推定的增强子 或针对私人和啮齿动物的进化枝特定的，其中富含SUD人类遗传风险变异。 该提案包括以下目的：目标1：确定私有式的配置单元格类型和标记 富含人类SUS风险变异的基因谱。目标2：确定主要构成的假定 增强子概况测试小鼠物质使用行为风险基因座是否破坏了类似的假定保守 人类SUD风险基因座的增强剂。这些实验共同揭示了主要的基因和增强子 通过整合单核基因组学，保守和规格的特定细胞类型的地图集 多种哺乳动物物种的数据。这些信息至关重要，因为更好地理解 关于个人的遗传构成如何影响奖励电路的细胞将为未来的工作提供帮助 个性化的，有针对性的SUD疗法。那，这项工作与我对成瘾的临床兴趣紧密融合 药品。该提案概述了严格的门将研究培训，纵向临床的结合 经验，课程以及专业和领导力发展活动。知地，技术， 在此奖学金培训期间，专业技能将在我的发展中发挥作用 成瘾医学临床领域有抱负的身体科学家。