Epigenomic approaches to study the gene networks underlying the cannabis effects on genetic vulnerability to psychosis

项目摘要/摘要 在过去的十年里，美国非法物质的使用在大多数情况下都有所减少 毒品，除了大麻，7.5%的人仍然最常滥用大麻 人口，特别是青少年。新出现的证据表明 大麻暴露和精神错乱风险增加。然而，精确的遗传和 支撑这种联系的分子成分在很大程度上仍未解决。 这项研究计划的长期目标是使用精神分裂症的啮齿动物模型 针对Reelin通路的敏感性，以研究复杂的多因素 大麻-精神病协会的性质，其最终目标是发展预防性 以及大麻使用障碍的治疗策略。 作为实现这一目标的第一步，能够选择性地分离出 将产生特定的神经元亚型。基于行为的综合战略 范例和表观基因组图谱，将被用来测试是否和在多大程度上 大麻的不同成分(如D9-四氢大麻酚和大麻二酚)会影响 观察到与认知障碍相关的特定行为的发展 精神分裂症。广泛的转录和表观基因组学工具，基于NEXT- 世代测序技术，将被应用于研究分子变化 是由大麻暴露引起的。全基因组的广泛生物信息学分析 该项目生成的数据集可能会为未来的研究奠定基础 侧重于支持大麻使用的新的神经表观遗传机制的项目 精神错乱。

Project Summary/Abstract Over the last decade, use of illicit substances in United States has decreased for most drugs, except for marijuana that remains the most commonly abused by 7.5% of the population, especially among adolescents. Emerging evidence indicates a link between cannabis exposure and elevated risk of psychosis. However, the precise genetic and molecular components underpinning this association remain largely unresolved. The long-term goal of this research program is to use rodent models of schizophrenia susceptibility, targeting the Reelin pathway, to investigate the complex multifactorial nature of cannabis-psychosis association, with the ultimate goal of developing preventive and therapeutic strategies for cannabis use disorders. As the first step toward this goal, animal models that enable the selective isolation of specific neuronal subtypes will be generated. An integrated strategy, based on behavioral paradigms and epigenomic profiling, will be used to test whether and to what extent different components of cannabis (e.g D9-tetrahydrocannabinol and cannabidiol) affect the development of specific behaviors relevant to cognitive impairments observed in schizophrenia. A wide range of transcriptomic and epigenomic tools, based on next- generation sequencing technologies, will be applied to investigate the molecular changes induced by cannabis exposure. Extensive bioinformatics analysis of the genome-wide datasets generated by this project will likely lay the groundwork for future research programs focused on novel neuroepigenetic mechanisms underpinning cannabis use disorders.