FETAL ALCOHOL SYNDROME: GENETIC STUDIES IN ZEBRAFISH

本申请将作为小额拨款（R03）提交考虑。我是一名新的研究者，计划扩大我的研究重点，包括乙醇诱导出生缺陷的领域。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，见于一些通过母亲饮酒而暴露于酒精的新生儿，其特征是产前和产后发育不良、中枢神经系统紊乱以及影响心血管系统、面部结构和四肢的一组独特的模式缺陷。来自双胞胎研究和动物模型的数据有力地证明了FAS的遗传成分。我们的假设是，单个基因的突变影响了一个人对乙醇诱导的致畸的抵抗力。斑马鱼脊椎动物模型系统已被证明在识别特定生理事件中起作用的基因方面是非常强大的。本提案的具体目标是：[1]分析乙醇在选定的斑马鱼品系中的非致死性致畸效应，[2]绘制并分离出包含斑马鱼品系对乙醇暴露的胚胎致死效应的不同敏感性基因的基因组区域。比较敏感和耐药的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。本文所述项目的最终成果将是彻底表征乙醇暴露对斑马鱼的非致命性致畸效应，这是FAS的特征，并鉴定几个包含影响斑马鱼对乙醇暴露影响敏感性的候选基因的大基因组克隆。

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.