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

项目总结/摘要 在过去的十年中，美国非法药物的使用在大多数情况下都有所减少。 毒品，除了大麻，大麻仍然是最常见的滥用7.5%的 人口，尤其是青少年。新出现的证据表明， 大麻暴露和精神病风险增加。然而，精确的基因和 支持这种关联的分子组分仍然在很大程度上未得到解决。 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 敏感性，靶向Reelin途径，以研究复杂的多因素 大麻与精神病之间的联系，最终目标是开发预防性药物， 和大麻使用障碍的治疗策略。 作为实现这一目标的第一步，动物模型，使选择性分离， 将产生特定的神经元亚型。基于行为的综合战略 范例和表观基因组分析，将用于测试是否以及在多大程度上 大麻的不同成分（例如D9-四氢大麻酚和大麻二酚）影响 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组学和表观基因组学工具，基于next- 第二代测序技术，将被应用于研究分子变化 是由大麻引起的对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为未来的研究奠定基础 重点关注支持大麻使用的新型神经表观遗传机制的项目 紊乱

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.