Role of Neuroinflammation in Behavioral Deficits Resulting from Chronic Alcohol

描述(由申请人提供)： 此指导培训计划将为申请人(Clare Wilhelm，Ph.D.)通过在免疫学、基因表达谱和酒精蒸气吸入方法方面的培训和技能，他将促进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有关的及时和关键的ISIS。候选人的发展将通过定向阅读和与申请者导师的讨论、教学研究和与酒精暴露模型、基因表达谱和免疫组织化学相关的动手实验培训来完成。完成后，申请者将处于有利地位，以实现他的长期职业目标，即开发更有效的酒精和药物滥用治疗方法。他致力于学术研究事业，并渴望开发自己的独立研究项目。波特兰退伍军人医学中心(PVAMC)和俄勒冈健康与科学大学(OHSU)的结合环境为这一提议提供了理想的环境。OHSU提供的特定课程作业与拟议的项目高度相关，并将有助于申请者的发展。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。与该项目相关的著名地方部门还包括：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博士和Hinrichs博士)拥有酒精滥用、性别和遗传差异、基因表达谱、免疫学、神经炎症和神经毒性方面的背景和经验，这些背景和经验将确保科学和职业发展计划的成功。酗酒/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。酗酒的人往往会患上脑损伤，这种损伤可以在饮酒消退后很长一段时间内持续下去，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性级联反应的激活增加。我们的初步数据表明，有神经毒性的动物和没有神经毒性的动物之间存在明显的神经免疫差异。我们假设酒精引起的神经毒性是酒精暴露引起的神经炎性反应级联反应的结果。为了探索这一假设，我们将使用酒精诱导的神经毒性(雌性戒断发作倾向(WSR)动物)和酒精诱导的神经保护(雄性WSR动物)的小鼠模型。神经毒性和神经炎症将通过免疫组织化学检查外周免疫细胞的渗透，基因表达谱确定神经元完整性的变化，以及苏木精-伊红和银染检查神经毒性。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，这些信息可能导致发现或开发治疗酒精滥用/依赖障碍的新疗法。

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.