Microglial Modulation of Nicotine Dependence

小胶质细胞对尼古丁依赖性的调节

基本信息

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
项目类别：
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

项目摘要

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。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的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。