FETAL ALCOHOL SYNDROME: GENETIC STUDIES IN ZEBRAFISH

本申请作为小额赠款(R03)提交审议。我是一名新的调查员，计划扩大我的研究重点，将乙醇导致的出生缺陷纳入其中。该项目的长期目标是阐明乙醇扰乱胚胎和胎儿发育的分子机制，并识别在乙醇诱导的畸形敏感性中发挥作用的基因。胎儿酒精综合征(FAS)是一组先天性异常，一些新生儿通过母体饮酒而暴露在酒精中，其特征是产前和出生后发育不良，中枢神经系统障碍，以及一组独特的图案缺陷，影响心血管系统、面部结构和四肢。来自双胞胎研究和动物模型的数据有力地证明了Fas具有强大的遗传成分。我们的假设是，单基因突变会影响一个人对酒精致畸的抵抗力。斑马鱼脊椎动物模型系统已被证明在识别在特定生理事件中发挥作用的基因方面非常强大。这项建议的具体目的是：[1]分析乙醇对选定的斑马鱼品系的非致死性致畸作用，以及[2]定位和分离包含导致斑马鱼品系对酒精暴露的胚胎致死效应的差异敏感性基因(S)的基因组区域(S)。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的遗传和分子机制，并可能直接适用于人类的酒精敏感。该项目的最终成果将是对乙醇暴露对斑马鱼的非致命性致畸作用的彻底表征，这是Fas的特征，并鉴定几个包含影响斑马鱼对乙醇暴露效应敏感性的候选基因的大型基因组克隆。

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.