SCF/c-Kit受体在药物依赖中神经生物学机制及作为治疗新靶点的研究

Opiates dependence is a very serious public health problem all over the world. The main problem of treatment is how to disrupt the persistent drug reward memory for preventing the craving after long-term withdrawal. It is well known that mesolimbic reward circuit is the final common pathway for these drugs to produce reward effect, which combines with reward memory leads to intensive craving eventually relapse. Neuroadaptations, including protein synthesis, in this circuit play critical role in addiction. The stem cell factor receptor/c-Kit signaling widely distributes in the central nervous system and activates the PKA, ERK，PI3K-AKT-mTOR signaling pathway involved in the regulation of neurogenesis. However, the role of SCF/c-Kit receptor involved in opiate drug dependence is still unclear. Our previous study suggested that inhibition of the SCF/c-Kit receptor activation could prevent the acquisition of conditioned place preference and expression after withdrawal. These results indicated that SCF/c-Kit receptor maybe play an important role in the drug reward memory, craving and relapse. Therefore, using the conditioned place preference animal model, we will explore the role of SCF/c-Kit receptor in the mesolimbic dopamine system for the drug reward memory, craving and relapse. The performance of this project will help us better understanding the mechanism of drug addiction, and preventing craving for drug addiction treatment.

阿片类药物依赖是中国重大公共社会卫生问题。药物作用于中脑边缘多巴胺系统激活相应受体、活化功能蛋白、产生奖赏效应；同时激活细胞内信号通路包括PKA、AKT、ERK等，调节基因转录和蛋白合成，参与长期神经可塑性发生，形成持久不易消除的奖赏记忆和心理渴求。SCF/c-Kit受体广泛分布中枢神经系统，通过激活PKA、AKT、ERK等信号通路参与神经发生，而在药物依赖中的作用未见报道。申请者前期研究发现，采用c-Kit受体抑制或c-Kit突变的方法，可阻断吗啡条件位置偏爱形成并消除奖赏记忆，说明其在阿片药物依赖中具有重要作用，由此获得c-Kit作为药物依赖治疗靶标的专利1项。因此，本项目将进一步系统研究中脑边缘多巴胺系统SCF/c-Kit受体在阿片类药物依赖中的神经生物学机制，并从分子、细胞和整体水平诠释该靶标分子的作用机制。

麻精药品与其他物质成瘾困扰人类几千年，是全球亟待解决的社会顽疾。本课题组通过系列实验发现中枢伏隔核c-Kit受体独立介导成瘾形成与复吸的过程，干预其活性可阻断成瘾的形成与复发，并通过系列实验确证其作为成瘾防治靶点的可行性，具有很好的靶标有效性与特异性。在此基础上，发现甲磺酸伊马替尼可靶向进入中枢伏隔核特异性与c-Kit受体结合抑制其活性达到预防与治疗的效果，现即将进入临床试验阶段。研究还发现，在成瘾的形成与阻断过程中中枢伏隔核c-Kit受体活性与外周肾组织及外周血液外泌体中c-Kit活性变化趋势一致，表明伏隔核c-Kit受体具有作为成瘾防治靶标及外周组织、血液外泌体中c-Kit具有作为成瘾诊疗监测特异性生物标志物的潜在可行性。从而突破成瘾防治靶标“卡脖子”技术，进一步研发靶向成瘾防治新药、麻精创新药以及精准诊疗监测等系列产品。若能成功上市，将改变现有麻精药品研发与临床应用市场格局，创造巨大经济与社会效益。