Role of Neuroinflammation in Behavioral Deficits Resulting from Chronic Alcohol

神经炎症在慢性酒精引起的行为缺陷中的作用

• 批准号: 8333153
• 负责人: CLARE J WILHELM
• 金额: --
• 依托单位: PORTLAND VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8333153
• 关键词: Abstinence; Alcohol abuse; Alcohol withdrawal syndrome; Alcohol-Induced Neurotoxicity; Alcohols; Alzheimer' s Disease; Animals; Area; Behavioral; Brain; Brain Injuries; Breathing; Cells; Chronic; Cognition; Commit; Control Animal; Data; Dependence; Development; Development Plans; Disease; Doctor of Philosophy; Drug abuse; Ensure; Environment; Ethanol; Exhibits; Female; Gene Expression Profiling; Genes; Genetic; Goals; Hand; Healed; Health Sciences; Hematoxylin and Eosin Staining Method; Human; Immune; Immune Cell Activation; Immune response; Immunohistochemistry; Immunology; Impairment; Individual; Infiltration; Inflammatory; Literature; Measures; Medical center; Mentors; Methamphetamine; Methods; Microbiology; Modeling; Molecular; Mus; Neurology; Neurons; Neurosciences; Oregon; Outcome; PTPRC gene; Pathway interactions; Peripheral; Population; Positioning Attribute; Psychiatry; Reading; Receptor Signaling; Recording of previous events; Recovery; Relapse; Research; Resistance; Role; Scientist; Seizures; Silver Staining; Structure; Surveys; Therapeutic; Time; Training; Treatment Efficacy; Universities; Up-Regulation; Veterans; Withdrawal; Work; alcohol abuse therapy; alcohol exposure; alcohol response; base; beta-Chemokines; brain size; career; career development; cell type; chemokine receptor; cohort; cost; drinking; effective therapy; executive function; experience; gene repression; healing; immune activation; improved; insight; male; mouse model; neurochemistry; neuroinflammation; neuroprotection; neurotoxic; neurotoxicity; new therapeutic target; novel therapeutics; programs; sex; skills training; socioeconomics; success; trafficking; vapor

DESCRIPTION (provided by applicant): This mentored training proposal will provide the applicant (Clare Wilhelm, Ph.D.) with training and skills in immunology, gene expression profiling, and alcohol vapor inhalation methods that will facilitate his transition to an independent scientist, while exploring timely and critical isses related to alcohol abuse, neuroinflammation and neurotoxicity. Candidate development will be accomplished through directed readings and discussions with the applicant's mentors, didactic studies, and hands on experimental training related to models of alcohol exposure, gene expression profiling, and immunohistochemistry. Upon completion, the applicant will be well positioned to pursue his long-term career goal of developing more efficacious treatments for alcohol and drug abuse. He is committed to a career in academic research and aspires to develop his own independent research program. The combined environments of the Portland VA Medical center (PVAMC) and Oregon Health & Science University (OHSU) provide an ideal environment for this proposal. Specific course work available at OHSU is highly relevant to the proposed project and will contribute to the applicant's development. The research environments of these venues are particularly strong, with alcohol-, methamphetamine-, and Alzheimer's disease research centers and the availability of numerous potential collaborators and consultants. Distinguished local departments are also available related to this project including: Behavioral Neuroscience, Neurology, Psychiatry and Molecular Microbiology and Immunology. The mentors (Drs. Wiren and Quinn) and consultants (Drs. Loftis and Hinrichs) possess the backgrounds and experiences in alcohol abuse, sex and genetic differences, gene expression profiling, immunology, neuroinflammation and neurotoxicity that will ensure the success of the scientific and career development plans. Alcohol abuse/dependence remains one of the most costly diseases in the U.S.A. and is particularly common in the veteran population. Effective treatments are lacking. Individuals that abuse alcohol often develop brain damage which can persist long after drinking has subsided, contribute to relapse and reduce treatment efficacy. Studies in mice have identified differences in neurotoxicity following chronic alcohol exposure. Humans with an alcohol abuse history exhibit increased activation of neuroinflammatory cascades in several brain areas. Our preliminary data suggests distinct neuroimmune differences between animals exhibiting neurotoxicity and those that do not. We hypothesize that alcohol-induced neurotoxicity is the result of activation of neuroinflammatory cascades in response to alcohol exposure. To explore this hypothesis, we will use mouse models of alcohol-induced neurotoxicity (female withdrawal seizure prone (WSR) animals) and alcohol-induced neuroprotection (male WSR animals). Neurotoxicity and neuroinflammation will be examined using immunohistochemistry to examine infiltration of peripheral immune cells, gene expression profiling to determine changes in neuronal integrity, and hematoxylin and eosin and silver staining to examine neurotoxicity. This project will provide important new information on alcohol-induced changes in brain neurochemistry that may result in the identification or development of novel therapeutics to treat alcohol abuse/dependence disorders. PUBLIC HEALTH RELEVANCE: Alcohol abuse has tremendous socioeconomic costs. The veteran population exhibits an increased propensity to develop abuse/dependence disorders. This proposal will lay the groundwork for the development of new immune-based therapeutics for alcohol abuse. In addition, this study will provide critical new insight into the role of neuroinflammation in alcoho-induced neurotoxicity. The identification of new pathways to heal brain damage induced by chronic alcohol abuse is critically needed.

描述（由申请人提供）： 该指导培训计划将为申请人（克莱尔威廉博士）提供在免疫学，基因表达谱和酒精蒸汽吸入方法方面的培训和技能，将有助于他向独立科学家的过渡，同时探索与酒精滥用，神经炎症和神经毒性相关的及时和关键问题。候选人的发展将通过定向阅读和与申请人的导师讨论，教学研究，以及与酒精暴露，基因表达谱和免疫组织化学模型相关的实验培训。完成后，申请人将有能力追求他的长期职业目标，即开发更有效的治疗酒精和药物滥用的方法。他致力于学术研究的职业生涯，并渴望发展自己的独立研究计划。波特兰VA医疗中心（PVAMC）和俄勒冈州健康与科学大学（OHSU）的综合环境为该提案提供了理想的环境。OHSU提供的具体课程工作与拟议项目高度相关，并将有助于申请人的发展。这些场所的研究环境特别强大，有酒精，甲基苯丙胺和阿尔茨海默病研究中心，以及许多潜在的合作者和顾问。杰出的当地部门也可与此项目相关，包括：行为神经科学，神经病学，精神病学和分子微生物学和免疫学。导师（Wiren和Quinn博士）和顾问（Loftis和Hinrichs博士）拥有酗酒，性别和遗传差异，基因表达谱，免疫学，神经炎症和神经毒性的背景和经验，这将确保科学和职业发展计划的成功。酒精滥用/依赖仍然是美国最昂贵的疾病之一，在退伍军人中尤其常见。缺乏有效的治疗方法。滥用酒精的人往往会出现脑损伤，这种损伤在饮酒后很长时间内都会持续下去，导致复发并降低治疗效果。对小鼠的研究已经确定了慢性酒精暴露后神经毒性的差异。有酗酒史的人在几个大脑区域表现出神经炎症级联反应的激活增加。我们的初步数据表明，在表现出神经毒性的动物和没有表现出神经毒性的动物之间存在明显的神经免疫差异。我们推测酒精诱导的神经毒性是酒精暴露后神经炎症级联反应激活的结果。为了探索这一假设，我们将使用酒精诱导的神经毒性（雌性戒断性癫痫发作（WSR）动物）和酒精诱导的神经保护（雄性WSR动物）的小鼠模型。将使用免疫组织化学检查外周免疫细胞浸润，基因表达谱分析确定神经元完整性的变化，以及苏木精和伊红和银染色检查神经毒性和神经炎症。该项目将提供有关酒精引起的脑神经化学变化的重要新信息，这些信息可能导致识别或开发治疗酒精滥用/依赖障碍的新疗法。 公共卫生相关性： 酗酒会造成巨大的社会经济成本。退伍军人人口表现出更大的倾向于发展滥用/依赖性障碍。该提案将为开发新的基于免疫的酒精滥用疗法奠定基础。此外，这项研究将提供关键的新的洞察神经炎症的作用，酒精诱导的神经毒性。迫切需要确定新的途径来治愈慢性酒精滥用引起的脑损伤。