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（由适用提供）：烟草成瘾可能对个人和社会的健康和经济状况产生重大的负面影响。负责成瘾的烟草中的主要心理活性成分是尼古丁，也可以以类似的滥用潜力以替代形式（例如，电子烟中的蒸发液体）食用。不幸的是，当前可用于尼古丁依赖性的绝大多数可用药物治疗药在促进长期禁欲方面略有有效。这是存在着一种紧迫的需求，可以通过创新的方法/观点来确定热发展的新目标。有趣的是，脑脊液（CSF） - 神经元界面开始成为神经元功能和病理学的关键调节剂。脉络丛和CSF提供了丰富的信号分子来源，最近的报道发现了许多功能性microRNA（miRNA）的存在。对基因表达的表观遗传调节的过去投资集中在神经元内部的信号传导上。但是，我们认为需要扩大这种重点，以认识到通过细胞外环境的细胞间交流的重要性。在此提案中，我们将研究来自CSF的循环miRNA，并确定其在介导基因表达中的作用。此外，我们预测这将导致行为反应改变和尼古丁的消耗。通过确定这些新型的细胞外机制介导尼古丁增强和奖励，我们希望确定对人类吸烟者/尼古丁使用者烟草习惯持续存在的重要见解。此外，确定的循环miRNA具有作为尼古丁成瘾的生物标志物的潜力。还应注意的是，脉络丛被认为是通过CSF进入大脑的主要进入点，因此，对这些过程的越来越多的理解可能对其他人类状况（例如HIV/AIDS）的发病机理具有广泛的影响。总而言之，这些投资的发现必须有潜在地推进对药物滥用的表观遗传调节的领域，在此过程中，可能引起范式从细胞内关注神经元功能的范式转变，以在其他过程中识别细胞外机制的重要性。通过这些努力，我们可以实现我们确定开发更有效疗法以治疗尼古丁依赖性的新目标的总体目标。