MOLECULAR CHARACTERIZATION OF FETAL ALCOHOL SYNDROME PATHOGENESIS

胎儿酒精综合征（FAS）是精神疾病的主要原因之一。 世界上最迟钝的人 我们已经进行了分子和生物化学 进一步了解FAS的发病机制。 该技术 差异mRNA显示技术检测基因表达的变化， 在发育中的小鼠胚胎中的表达。 鼠标 胚胎也用另一种已知的致畸剂3- 甲基胆蒽（3-MC），以确定mRNA， 特别是乙醇。 进行北方印迹分析 以确认差异显示结果。 我们已经确定了两个 已知的和一个未知的cDNA，其相应的mRNA水平被改变 通过接触乙醇。 α-原肌球蛋白的一种脑特异性亚型 在11日龄的胚胎中，乙醇上调而3-MC不上调。 免疫印迹分析表明，α-原肌球蛋白的水平 蛋白质也因乙醇暴露而升高。 脑特异性同种型 已经证明α-原肌球蛋白对中枢神经系统的重要性， 系统发育及其在关键时期的异位表达 可能会破坏正常的发展，并导致一些 FAS中观察到的表型。 另一个已知的cDNA编码热休克蛋白 47（HSP 47），其参与前胶原蛋白加工。 表达 HSP 47基因的表达在成年大鼠中被缺血诱导 个脑袋 缺血被认为是FAS的一种可能机制， 已经证明，向猴子注射大剂量的乙醇会导致 脐带的塌陷和血流的减少 我们有 最近使用cDNA微阵列来鉴定额外的mRNA， 在FAS的早期阶段改变。 鉴定这些 mRNA将增加我们对致畸作用的理解， 乙醇和有效治疗的机会。

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.