Cerebellum Gene Expression Changes With Chronic Ethanol

慢性乙醇引起的小脑基因表达变化

• 批准号: 7055384
• 负责人: STEPHEN WALKER
• 金额: $ 16.64万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-20 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7055384
• 关键词: Macaca fascicularis; alcoholic beverage consumption; animal tissue; brain mapping; cerebellum; ethanol; gender difference; gene expression profiling; microarray technology; neurogenetics; self medication

DESCRIPTION (provided by applicant): The effects of chronic ethanol self-administration on global gene expression in the brain have not been extensively characterized. The majority of studies to examine brain gene expression have used rodent models, neuronal cells in culture, or tissue from archived human autopsy samples. While these studies have provided a wealth of information, the use of each of these model systems has limitations. The present study proposes to initiate a systematic analysis of ethanol-sensitive gene expression in relevant brain regions by starting with a brain region known to be affected by chronic ethanol consumption - the cerebellum. Although cerebellar involvement in movement related behaviors is well documented, there is a growing interest understanding the role of the cerebellum in the cognitive changes that occur in alcoholism. To investigate this question, this study will use a very unique and robust nonhuman primate model of chronic ethanol self administration developed at Wake Forest University. These experiments will be conducted with brain tissue from cynomolgus monkeys who have self-administered ethanol for 18 consecutive months at chronic levels (up to 4.0 g/kg/day). The advantages of using this model to investigate brain gene expression are threefold: (1) the close similarity of non-human primate to humans in terms of physiology, genetics, and consumption render it a very relevant model; (2) the entire (chronic) drinking history for these animals is known and; (3) the availability of tools (high density gene arrays) that permit the evaluation of whole-genome gene expression provide the possibility to achieve a level of gene expression analysis never before possible. The gene expression data generated from a within-subject design (examining three separate regions of the cerebellum in each animal), as well as a between-group design (comparison between chronic alcohol and alcoholna'fve; comparison between males and females) will provide significant new information. Identifying the molecular basis of neuropathology in the nonhuman primate brain resulting from chronic ethanol self-administration should have direct relevance to better understanding human alcoholism.

描述（由申请人提供）：长期自我施用乙醇对大脑中整体基因表达的影响尚未得到广泛表征。大多数检查大脑基因表达的研究都使用啮齿动物模型、培养的神经元细胞或来自存档的人体尸检样本的组织。虽然这些研究提供了丰富的信息，但每个模型系统的使用都有局限性。本研究建议从已知受长期乙醇消耗影响的大脑区域——小脑开始，对相关大脑区域的乙醇敏感基因表达进行系统分析。尽管小脑参与运动相关行为已有充分记录，但人们越来越有兴趣了解小脑在酗酒引起的认知变化中的作用。为了研究这个问题，本研究将使用维克森林大学开发的一种非常独特且强大的非人类灵长类动物慢性自我管理乙醇模型。这些实验将使用食蟹猴的脑组织进行，这些食蟹猴连续 18 个月以慢性水平（高达 4.0 克/公斤/天）自我施用乙醇。使用该模型研究大脑基因表达的优点有三个：（1）非人灵长类动物在生理、遗传学和消费方面与人类非常相似，使其成为一个非常相关的模型； (2) 这些动物的整个（长期）饮酒史是已知的； (3) 允许评估全基因组基因表达的工具（高密度基因阵列）的可用性提供了实现前所未有的基因表达分析水平的可能性。受试者内设计（检查每只动物小脑的三个独立区域）以及组间设计（慢性酒精和酒精中毒之间的比较；男性和女性之间的比较）生成的基因表达数据将提供重要的新信息。确定非人类灵长类动物大脑中因长期自我施用乙醇而导致的神经病理学的分子基础应该与更好地理解人类酒精中毒有直接关系。