FETAL ALCOHOL SYNDROME: GENETIC STUDIES IN ZEBRAFISH

此申请将作为小额赠款（R03）提交审议。我是一名新的研究者，计划扩大我的研究重点，包括乙醇引起的出生缺陷领域。该项目的长期目标是阐明乙醇干扰胚胎和胎儿发育的分子机制，并确定对乙醇诱导的致畸敏感性起作用的基因。胎儿酒精综合征（FAS）是一组先天性异常，见于一些新生儿通过母亲消费暴露于酒精，其特征是产前和产后发育不良，中枢神经系统疾病，以及一组影响心血管系统，面部结构和四肢的独特模式缺陷。来自双胞胎研究和动物模型的数据强烈支持FAS的强大遗传成分。我们的假设是，单个基因的突变影响一个人对乙醇诱导的致畸作用的抵抗力。斑马鱼脊椎动物模型系统已被证明是非常强大的目的，确定在特定的生理事件中发挥作用的基因。本提案的具体目的是：[1]分析乙醇在选定斑马鱼品系中的非致死致畸效应，[2]绘制并分离含有斑马鱼品系对乙醇暴露胚胎致死效应的差异敏感性基因的基因组区域。比较敏感和抗性斑马鱼品系将阐明脊椎动物胚胎对酒精毒性敏感性背后的遗传和分子机制，并可能直接应用于人类的酒精敏感性。本文描述的项目的最终产品将是一个彻底的表征非致死性致畸作用的乙醇暴露在斑马鱼的特征FAS，并确定几个大的基因组克隆含有候选基因，影响斑马鱼的敏感性乙醇暴露的影响。

This application is being submitted for consideration as a small grant (R03). I am a new investigator planning to expand my research focus to include the area of ethanol-induced birth defects. The long-range goal of this project is to elucidate the molecular mechanisms by which ethanol perturbs embryonic and fetal development and to identify genes that play a role in the sensitivity to ethanol-induced teratogenesis. Fetal Alcohol Syndrome (FAS) is a constellation of congenital anomalies seen in some newborns exposed to alcohol through maternal consumption and is characterized by prenatal and postnatal failure to thrive, central nervous system disorders, and a distinctive set of patterning defects that affect the cardiovascular system, facial structures and limbs. Data from twin studies and animal models argue strongly for a robust genetic component to FAS. Our hypothesis is that mutations in single genes influence one's resistance to ethanol-induced teratogenesis. The zebrafish vertebrate model system has proven to be very powerful for the purpose of identifying genes that play a role in specific physiological events. The specific aims of this proposal are to: [1] Analyze the non-lethal teratogenic effects of ethanol in selected zebrafish strains, and [2] Map and isolate the genomic region(s) containing the gene(s) responsible for the differential sensitivity of zebrafish strains to the embryolethal effects of ethanol exposure. Comparing sensitive and resistant zebrafish strains will elucidate the genetic and molecular mechanisms behind the sensitivity of vertebrate embryos to alcohol toxicity, and may apply directly to alcohol sensitivity in humans. The final products of the project described herein will be a thorough characterization of the nonlethal teratogenic effects of ethanol exposure in zebrafish that are characteristic of FAS, and the identification of several large genomic clones containing candidate genes that influence the sensitivity of zebrafish to the effects of ethanol exposure.