Circulating miRNAs and Epigenetic Regulation in Nicotine Addiction

 说明(申请人提供)：烟草成瘾对个人和社会的健康和经济状况造成严重的负面影响。烟草中导致上瘾的主要精神活性成分是尼古丁，尼古丁也可能以其他形式(例如，电子烟中的蒸发液体)以类似的滥用潜力被消费。不幸的是，目前可用的绝大多数尼古丁依赖药物疗法在促进长期戒断方面略有效果。因此，迫切需要通过创新的方法/观点来确定治疗发展的新目标。有趣的是，脑脊液(CSF)-神经元界面开始成为神经功能和病理的关键调节因素。脉络丛和脑脊液提供了丰富的信号分子来源，最近的报道发现存在大量的功能性microRNAs(MiRNAs)。过去对基因表达的表观遗传调控的研究主要集中在神经元内部的信号传递。然而，我们认为，这一重点需要扩大，以认识到通过细胞外环境进行细胞间通信的重要性。在这个方案中，我们将研究来自脑脊液的循环miRNAs，并确定它们在缰核中调节基因表达的作用。此外，我们预测这将导致行为反应和尼古丁消费的改变。通过识别这些调节尼古丁强化和奖励的新的细胞外机制，我们希望确定对人类吸烟者/尼古丁使用者持续吸烟习惯的重要见解。此外，已识别的循环miRNAs有可能作为尼古丁成瘾的生物标志物。还应该注意的是，脉络丛被认为是病毒通过脑脊液进入大脑的主要入口点，因此，对这些过程的深入了解可能对其他人类疾病的发病机制有广泛的影响，如艾滋病毒/艾滋病。总之，这些研究的结果有可能显著推进物质滥用的表观遗传调控领域，并且在这样做的过程中，可能会导致范式的转变，从关注成瘾过程中的神经元功能转向认识细胞外机制的重要性。通过这些努力，我们可能实现我们的首要目标，即为开发更有效的治疗尼古丁依赖的疗法确定新的靶点。

 DESCRIPTION (provided by applicant): Tobacco addiction imposes a significant negative impact on the health and economic status of the individual and society. The main psychoactive component in tobacco responsible for addiction is nicotine, which may also be consumed in alternate forms (e.g., vaporized liquid in e-cigarettes) with similar abuse potential. Unfortunatel, the vast majority of currently available pharmacotherapeutics for nicotine dependence are marginally effective in promoting long-term abstinence. Thus, a pressing need exists to identify novel targets for therapeutic development through innovative approaches/perspectives. Interestingly, the cerebrospinal fluid (CSF)-neuronal interface is beginning to emerge as a critical regulator of neural function and pathology. The choroid plexus and CSF provide a rich source of signaling molecules, and recent reports have uncovered the presence of a multitude of functional microRNAs (miRNAs). Past investigations into epigenetic regulation of gene expression have focused on signaling within the neurons themselves. However, we contend that this focus needs to be expanded to recognize the importance of intercellular communication via the extracellular environment. In this proposal, we will investigate circulating miRNAs from the CSF and establish their role in mediating gene expression in the habenula. Further, we predict that this will result in altered behavioral responses and consumption of nicotine. By identifying these novel extracellular mechanisms mediating nicotine reinforcement and reward, we hope to ascertain important insights into the persistence of the tobacco habit in human smokers/nicotine users. Moreover, identified circulating miRNAs have the potential to serve as biomarkers for nicotine addiction. It should also be noted that the choroid plexus is considered a main entry point for viral access into the brain via the CSF, and as such, an increased understanding of these processes may have broad implications for the pathogenesis of other human conditions, such as HIV/AIDS. In conclusion, findings from these investigations have to potential to significantly advance the field of epigenetic regulation of substance abuse, and in doing so, may induce a paradigm shift from an intracellular focus on neuronal function in addictive processes to recognize the importance of extracellular mechanisms. Through these efforts, we may achieve our overarching goal of identifying novel targets for the development of more efficacious therapeutics to treat nicotine dependence.