Circulating miRNAs and Epigenetic Regulation in Nicotine Addiction

尼古丁成瘾中的循环 miRNA 和表观遗传调控

• 批准号: 9089956
• 负责人: CHRISTIE D FOWLER
• 金额: $ 45.89万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9089956
• 关键词: AIDS/HIV problem; Abstinence; Biological Markers; Brain; Cerebrospinal Fluid; Consumption; Development; Electronic cigarette; Environment; Epigenetic Process; Foundations; Gene Expression; Goals; HIV; Habenula; Habits; Health; Human; Individual; Infiltration; Intake; Investigation; Liquid substance; Mediating; MicroRNAs; Neurons; Neurophysiology - biologic function; Nicotine; Nicotine Dependence; Pathogenesis; Pathology; Pharmaceutical Preparations; Process; Psychological reinforcement; Reporting; Research; Rewards; Role; Signal Transduction; Signaling Molecule; Smoker; Societies; Source; Structure of choroid plexus; Substance abuse problem; Therapeutic; Tobacco; Tobacco Dependence; Viral; addiction; behavioral response; circulating microRNA; epigenetic regulation; extracellular; health economics; innovation; insight; intercellular communication; novel; novel therapeutics; smoking cessation; therapeutic development

 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.

 描述（由申请人提供）：烟草成瘾对个人和社会的健康和经济状况产生重大负面影响。烟草中导致成瘾的主要精神活性成分是尼古丁，尼古丁也可以以其他形式（例如，电子烟中的汽化液体），具有类似的滥用潜力。不幸的是，绝大多数目前可用的尼古丁依赖药物在促进长期戒烟方面效果甚微。因此，迫切需要通过创新的方法/观点来确定用于治疗开发的新靶点。有趣的是，脑脊液（CSF）-神经元界面开始成为神经功能和病理学的关键调节因子。脉络丛和CSF提供了丰富的信号分子来源，最近的报道已经发现了许多功能性microRNA（miRNAs）的存在。过去对基因表达的表观遗传调控的研究集中在神经元本身的信号传导上。然而，我们认为，这一重点需要扩大到认识到通过细胞外环境的细胞间通信的重要性。在这个提议中，我们将研究来自CSF的循环miRNA，并确定它们在缰核中介导基因表达的作用。此外，我们预测这将导致行为反应和尼古丁消耗的改变。通过确定这些新的细胞外机制介导尼古丁的强化和奖励，我们希望确定重要的见解，在人类吸烟者/尼古丁使用者的烟草习惯的持久性。此外，已鉴定的循环miRNA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CSF进入大脑的主要入口点，因此，对这些过程的更多了解可能对其他人类疾病（如HIV/AIDS）的发病机制具有广泛的影响。总之，这些调查的结果有可能显着推进物质滥用的表观遗传调控领域，并在这样做，可能会引起一个范式的转变，从细胞内的重点神经元功能在成瘾过程中认识到细胞外机制的重要性。通过这些努力，我们可以实现我们的首要目标，即确定新的目标，以开发更有效的治疗尼古丁依赖的疗法。