Microglial Modulation of Nicotine Dependence

项目概要/摘要： 尽管在降低吸烟成年人的比例方面取得了很大进展， 吸烟者继续吸烟，30%的癌症与吸烟有关。尽管新戒烟 药物治疗，戒烟率保持在10%以下。一个主要的缺乏成功是由于尼古丁戒断 生物学。目前的研究表明，大脑中的神经胶质免疫反应和随后的免疫反应可能是神经胶质细胞的一个重要组成部分。 神经炎症可能是阴性病理学的基础。虽然神经炎症和相关的神经胶质增生 已被证明是许多神经系统疾病的主要介质，包括CNS创伤， 缺血、中风和神经退行性疾病，其在尼古丁依赖性烟草使用障碍中的作用， 没有被调查。小胶质细胞作为大脑的常驻免疫细胞，对大脑中的变化做出反应。 微环境和响应极化成促炎和抗炎状态。我们推测 减弱小胶质细胞增生会减少尼古丁引起的焦虑样反应， 戒断使用小鼠尼古丁依赖动物模型，我们将研究药理学 具有结构上和机理上不同的作用机制的化合物， 炎症小胶质细胞激活的减弱应该会减少在治疗过程中发生的焦虑样行为。 通过改善神经炎症反应和改变分泌的效应物来戒断尼古丁 分子景观这些变化将在行为和分子上进行探索，集中在小胶质细胞上。 形态学和效应分子测量（细胞因子和趋化因子）， 程度.小胶质细胞反应和信号传导的变化将增加对小胶质细胞反应机制的临床相关见解。 神经炎症作为尼古丁使用障碍的目标。这种创新的方法可以扩大 戒烟药物工具箱，每年减少700万人与烟草有关的死亡 通行费

Project Summary/Abstract: Notwithstanding great strides in lowering the percentage of smoking adults, close to a billion people a year continue to smoke and 30% of all cancers are linked to tobacco use. Despite new smoking cessation pharmacotherapies, quit rates remain at less than 10%. A major lack of success is due to nicotine withdrawal symptomology. Current research suggests glial immune responses in the brain and subsequent neuroinflammation may underlie the negative symptomology. While neuroinflammation and associated gliosis has been demonstrated to be a primary mediator of many neurological disorders, including in CNS trauma, ischemia, stroke, and neurodegenerative diseases, its role in nicotine dependence tobacco use disorder has not been investigated. The microglia as the resident immune cells of the brain respond to changes in the microenvironment and respond by polarization into proinflammatory and anti-inflammatory states. We postulate that attenuating microgliosis pharmacologically will reduce the anxiety-like responses during nicotine withdrawal. Using a mouse animal model of nicotine dependence, we will investigate pharmacological compounds possessing both structurally and mechanistically distinct mechanisms of action for inhibiting this inflammation. Attenuation of the microglial activation should reduce the anxiety-like behaviors occurring during nicotine withdrawal by ameliorating the neuroinflammatory response and altering the secreted effector molecules landscape. These changes will be probed behaviorally and molecularly, concentrating on microglial morphology, and effector molecule measurements (cytokine and chemokines) at both the gene and protein levels. Changes in microglial response and signaling will add clinically relevant insight into mechanisms for neuroinflammation as a target of nicotine use disorder. This innovative approach could expand the pharmacological toolbox for smoking cessation and reduce the 7 million people a year tobacco related death toll.