神经肽S受体基因变异对阿片成瘾的影响及其神经生物学机制研究

阿片成瘾是一种慢性、复杂性脑疾病，遗传因素是导致成瘾易感性高低的重要原因，同时影响患者对治疗干预的反应性。神经肽S受体（Neuropeptide S receptor，NPSR）是近年来新发现的去孤儿化G蛋白偶联受体，在人NPSR染色体中存在A/T单核苷酸多态性，流行病学研究提示此突变可能参与了药物成瘾的发生发展。但是，由于种属差异而导致的基因型差异，NPSR的A/T突变对于阿片成瘾的影响及其神经生物学机制尚不清楚。为了打破研究模型限制，本研究应用成瘾患者自然突变和CRISPR技术编辑突变的诱导性干细胞重编程为神经元，体内模型应用NPSR基因突变小鼠，研究NPS-NPSR系统对于阿片成瘾的影响及其神经生物学机制，评价NPSR配体的抗阿片成瘾药理学作用。本课题旨在明确NPSR基因突变在药物成瘾易感性方面的贡献以及NPS-NPSR系统的作用，将有助于监测成瘾易感人群和明确NPS精准治疗作用。

Opioid addiction is a chronic and complicated brain disorder. Genetic factor plays an important role in the addiction vulnerability and response for addiction treatment. Neuropeptide S receptor (NPSR) is a new discovered de-orphanized GPCR, and was found to have a single-nucleotide polymorphism (rs324981, A>T). Epidemiology study reported that this mutation in NPSR may be associated with the development of drug addiction. However, due to the species difference, it is unclear about the impact of NPSR on opioid addiction and its neurobiological mechanism. In order to break the limitation of experimental model, pluripotent stem cells (iPSC) derived from the addiction patients will be used to be mutated by CRISPR and then induced into the indicated neurons. Furthermore, we will take advantage of the NPSR gene mutation mice to study the effect of NPS-NPSR system on opioid addiction and the underlying neurobiological mechanism. The study would help to clarify the contribution of NPS-NPSR system in opioid addiction, which would conducive to the supervision and precision medicine for the abusers.