Microglial Modulation of Nicotine Dependence

小胶质细胞对尼古丁依赖性的调节

• 批准号: 9976881
• 负责人: Erin Leigh Anderson
• 金额: $ 5.4万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9976881
• 关键词: Abstinence; Adult; Affect; Affective Symptoms; Animal Model; Animals; Anti-Inflammatory Agents; Antiinflammatory Effect; Anxiety; Apoptotic; Attenuated; Behavioral; Biochemical; Biological Assay; Brain; Brain region; Cell Nucleus; Cells; Cessation of life; Characteristics; Chronic; Corpus striatum structure; Cytokine Receptors; Data; Disease; Drug Targeting; Drug usage; Equilibrium; Gene Proteins; Generations; Gliosis; Growth Factor; Imaging Techniques; Immune; Immune response; Inflammation; Inflammatory; Ischemia; Link; Malignant Neoplasms; Marble; Measurement; Mediating; Mediator of activation protein; Microglia; Minocycline; Molecular; Morphology; Mus; Myelogenous; Myeloid Cells; Neurodegenerative Disorders; Neurology; Nicotine; Nicotine Dependence; Nicotine Use Disorder; Nicotine Withdrawal; Nucleus Accumbens; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phenotype; Property; Psychiatry; Reporting; Research; Rest; Role; Signal Transduction; Smoke; Smoker; Smoking; Stroke; Structure; Substance Use Disorder; Substance abuse problem; Surgeon; Synaptic Transmission; TLR4 gene; TNF gene; Tetracyclines; Therapeutic; Tissues; Tobacco; Tobacco Use Disorder; Tobacco smoking behavior; Tobacco use; Traumatic CNS injury; United States; Ventral Striatum; Withdrawal; Withdrawal Symptom; antimicrobial; anxiety-like behavior; attenuation; behavioral phenotyping; brain cell; chemokine; clinically relevant; cytokine; experience; field study; fluorescence imaging; immunoregulation; improved; inhibitor/antagonist; innovation; insight; mRNA Expression; mouse model; nervous system disorder; neuroinflammation; nicotine use; novel; prevent; preventable death; protein expression; receptor; response; sex; smoking cessation; success; symptomatology; therapeutic target; tool; withdrawal-induced anxiety

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.

项目摘要/摘要： 尽管在降低成年人吸烟比例方面取得了巨大进步，但每年仍有近十亿人吸烟 继续吸烟，30% 的癌症与烟草使用有关。尽管新戒烟 药物治疗的戒烟率仍低于 10%。缺乏成功的主要原因是尼古丁戒断 症状学。目前的研究表明大脑中的神经胶质细胞免疫反应以及随后的反应 神经炎症可能是阴性症状的基础。而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，包括中枢神经系统创伤， 缺血、中风和神经退行性疾病，其在尼古丁依赖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，对环境的变化做出反应 微环境并通过极化反应进入促炎和抗炎状态。我们假设 药理学上减轻小胶质细胞增生将减少尼古丁期间的焦虑样反应 撤回。使用尼古丁依赖的小鼠动物模型，我们将研究药理学 具有结构和机制上不同的作用机制的化合物可以抑制这种情况 炎。小胶质细胞激活的减弱应该会减少在 通过改善神经炎症反应和改变分泌效应器来戒断尼古丁 分子景观。这些变化将从行为和分子角度进行探讨，重点关注小胶质细胞 基因和蛋白质的形态学和效应分子测量（细胞因子和趋化因子） 水平。小胶质细胞反应和信号传导的变化将增加对机制的临床相关见解 神经炎症是尼古丁使用障碍的目标。这种创新方法可以扩大 戒烟药理学工具箱，每年减少 700 万人与烟草相关的死亡 收费。