Sage in Cerebellum After Alcohol Exposure

酒精暴露后小脑的圣人

• 批准号: 6795306
• 负责人: ANDREJ ROTTER
• 金额: $ 7.38万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-01 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6795306
• 关键词: alcoholic beverage consumption; alcoholic beverages; brain injury; cerebellum; cytotoxicity; gene expression; genetic library; genetic mapping; informatics; laboratory mouse; mature animal; neurogenetics; newborn animals; nucleic acid sequence; serial analysis of gene expression

DESCRIPTION (provided by applicant): Excessive consumption of alcohol is known to have toxic effects on the fetal, adult and aging nervous system. It is well established that cerebellar neurons are subject to the damaging effects of alcohol administration throughout development. Because the major function of the cerebellum is to modulate movement and balance by integrating sensory input and motor output, any injury to component neurons is likely to lead to the impairment of motor co-ordination. It is plausible that alcohol-induced cerebellar damage is the result of cumulative changes in the expression of many genes. To date, only a fraction of the genes comprising the human and mouse genomes have been assayed for alcohol-induced changes, either individually or by DNA microarrays. Because DNA microarray technology is a 'closed' system, capable of detecting only known genes, we propose to conduct a global analysis of gene expression in the alcohol-exposed mouse cerebellum using Serial Analysis of Gene Expression (SAGE). SAGE is an 'open' system capable of detecting and digitally quantifying both known and, as yet, unknown genes. The proposed experiments involve the construction, sequencing and bioinformatic analysis of routine cerebellar SAGE libraries during the early postnatal period, adulthood and senescence, shortly after exposure to "binge" amounts of alcohol. The resulting comprehensive and quantitative SAGE database of alcohol-induced changes in gene expression, which includes that of novel genes, will be disseminated via the NCBI website. Future long-term experiments, beyond the scope of this R03 and proposed as part of a planned R01 submission, will be aimed at (1) construction of "timed" cerebellar SAGE libraries at several time intervals after alcohol exposure; (2) preparation of cerebellar SAGE libraries from mice chronically exposed to alcohol; (3) the full characterization of novel cerebellar genes whose expression is substantially altered as a result of alcohol administration, and (4) the examination of experimental strategies aimed at reversing the toxic effects of alcohol ingestion on cerebellar neurons.

描述（由申请人提供）：已知过量饮酒对胎儿、成人和衰老的神经系统有毒性作用。众所周知，小脑神经元在整个发育过程中都会受到酒精的损害。由于小脑的主要功能是通过整合感觉输入和运动输出来调节运动和平衡，因此对组成神经元的任何损伤都可能导致运动协调的损害。酒精引起的小脑损伤是许多基因表达累积变化的结果，这似乎是合理的。到目前为止，只有一小部分的基因组成的人类和小鼠基因组已被测定酒精诱导的变化，无论是单独或通过DNA微阵列。由于DNA微阵列技术是一个“封闭”的系统，能够检测已知的基因，我们建议进行一个全球性的分析，在酒精暴露的小鼠小脑基因表达的基因表达序列分析（SAGE）。SAGE是一个“开放”的系统，能够检测和数字量化已知和未知的基因。拟议的实验涉及在出生后早期，成年和衰老期间，暴露于“狂欢”酒精量后不久，常规小脑SAGE库的构建，测序和生物信息学分析。由此产生的酒精诱导的基因表达变化的全面和定量SAGE数据库，其中包括新基因，将通过NCBI网站传播。未来的长期实验，超出了本R 03的范围，并作为计划的R 01提交的一部分，将旨在（1）在酒精暴露后的几个时间间隔构建“定时”小脑SAGE文库;（2）从长期暴露于酒精的小鼠制备小脑SAGE文库;（3）新的小脑基因的完全表征，其表达由于酒精施用而显著改变，以及（4）旨在逆转酒精摄入对小脑神经元的毒性作用的实验策略的检查。