MOLECULAR CHARACTERIZATION OF FETAL ALCOHOL SYNDROME PATHOGENESIS

胎儿酒精综合征发病机制的分子特征

• 批准号: 6160366
• 负责人: B J SONG
• 金额: --
• 依托单位: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6160366
• 关键词: brain metabolism; complementary DNA; developmental neurobiology; disease /disorder etiology; embryo /fetus cell /tissue; embryo /fetus drug adverse effect; ethanol; fetal alcohol syndrome; ischemia; laboratory mouse; messenger RNA; methylcholanthrene; molecular pathology; northern blottings; protein isoforms; stress proteins; teratogens; tropomyosin; western blottings

Fetal alcohol syndrome (FAS) is one of the leading causes of mental retardation in the world. We have undertaken a molecular and biochemical approach towards understanding the pathogenesis of FAS. The technique of differential mRNA display was used to detect changes in gene expression in developing mouse embryos caused by ethanol exposure. Mouse embryos were also treated with another known teratogen, 3- methylcholanthrene (3-MC), in order to identify mRNAs which are specifically regulated by ethanol. Northern blot analyses were performed to confirm the differential display findings. We have identified two known and one unknown cDNA whose corresponding mRNA levels are altered by exposure to ethanol. A brain specific isoform of alpha-tropomyosin is up-regulated by ethanol but not by 3-MC in 11-day old embryos. Immunoblot analyses indicate that the level of the alpha-tropomyosin protein is also elevated by ethanol exposure. The brain specific isoform of alpha-tropomyosin has been shown to be important for central nervous system development and its ectopic expression during a critical period of development may disrupt normal development and cause some of the phenotypes seen in FAS. The other known cDNA encodes heat shock protein 47 (HSP47) which is involved in pro-collagen processing. The expression of the HSP47 gene was shown to be induced by ischemia in the adult rat brain. Ischemia has been noted as a possible mechanism of FAS as it has been shown that injection of bolus doses of ethanol into monkeys causes the collapse of the umbilical cord and decreased blood flow. We have recently used cDNA microarrays to identify additional mRNAs, which are altered during the early stages of FAS. The identification of these mRNAs will increase our understanding of the teratogenic actions of ethanol and the chances for effective treatment.

胎儿酒精综合征(FAS)是精神疾病的主要原因之一 世界上的智障。我们已经进行了一项分子和生化研究 探讨Fas的发病机制。这项技术 用差异显示技术检测基因的变化 乙醇暴露所致小鼠胚胎发育过程中的表达。小白鼠 胚胎也用另一种已知的致畸剂3- 甲基胆蒽(3-MC)，以识别哪些是 具体由乙醇控制。进行了Northern杂交分析 以确认差异显示结果。我们已经确认了两个 已知的和一个未知的基因，其相应的mRNA水平发生了变化 暴露在乙醇中。脑特异性α-原肌球蛋白亚型 在11天大的胚胎中被乙醇上调，但不被3-MC上调。 免疫印迹分析表明，α-原肌球蛋白水平 酒精暴露也会增加蛋白质的含量。脑特异性异构体 已证明α-原肌球蛋白对中枢神经系统很重要 关键时期的制度发展及其异位表达 可能会扰乱正常的发展，并导致一些 Fas的表型。另一个已知的cdna编码热休克蛋白。 47(HSP47)，参与前胶原蛋白的加工。表达方式 HSP47基因在成年大鼠脑缺血中的表达 大脑。缺血被认为是Fas的一个可能机制，因为它 研究表明，向猴子体内注射大剂量的乙醇会导致 脐带的塌陷和血流量的减少。我们有 最近使用cDNA微阵列识别额外的mRNAs，这些mRNAs 在FAS的早期阶段发生了改变。这些人的身份 MRNAs将增加我们对致畸作用的理解 乙醇和有效治疗的机会。