Response Signatures of Alcohol-Related Birth Defects

胎儿酒精综合症（FAS）是指一种公认的出生缺陷模式，发生在怀孕期间饮酒的妇女所生的一部分儿童中。典型的酒精相关出生缺陷包括小脑畸形、小眼、面部突出和内脏弓的缺陷，以及对心脏、大血管和胸腺的影响。了解产前酒精暴露的疾病机制取决于了解代谢和调节途径介导导致畸形发生的关键步骤。本研究利用基因表达阵列和生物信息学技术在急性动物模型中探讨酒精相关出生缺陷的起源。人类酒精相关出生缺陷的许多疾病终点可在C57BL/6J小鼠的原肠胚发育-神经发育阶段急性诱导。特异性目标1将调查酒精相关出生缺陷中常见畸形结构的正常（发育）基因表达。参数化将通过对急性妊娠期乙醇暴露有不同反应的小鼠C7BL/6J和CD-1品系，对乙醇诱导的致畸易感性窗口（妊娠8-10天）的眼部和后脑发育的关键阶段进行里程碑式的研究。传统的显微解剖和激光捕获显微解剖将从测试和参考样品中分离出特定的前体靶细胞群。特异性目标2将列举暴露-疾病连续体中与酒精相关的基因表达变化。参数化将涉及剂量反应、暴露后时间和敏感性不同的菌株。重点是在妊娠第9天暴露发育中的眼睛和后脑。具体目标3是启动一个功能基因组学/计算生物学管道，用于全面的模式识别，探索和验证酒精在发育靶器官中的相关变化。微阵列数据将被合并到第一个基因表达参考数据库中，用于检测酒精对发育中的胚胎的相关影响。这一努力将使代表疾病机制核心现象的关键反应特征的计算成为可能。通过研究多基因反应特征，我们希望确定在产前乙醇暴露的关键时期，各种代谢和调节途径陷入混乱。最后，我们期望这些知识将使研究人员能够确定酒精相关出生缺陷的机制和非侵入性干预策略。项目产生的资源将包括设计和构建专门的阵列，重点关注对乙醇中毒有反应的基因，以及通过全球网络向科学界提供的关系数据库。

Fetal alcohol syndrome (FAS) refers to a recognized pattern of birth defects that occurs in a subset of children born to women who consume alcohol during pregnancy. Typical alcohol- related birth defects include microencephaly, microphthalmia, deficiencies of the facial prominences and visceral arches, as well as effects on the heart, great vessels, and thymus. Understanding disease mechanisms in prenatal alcohol exposure depends upon learning what metabolic and regulatory pathways mediate critical steps leading to dysmorphogenesis. The research proposed here uses gene expression arrays and bioinformatics to probe the origins of alcohol-related birth defects in an acute animal model. Many disease endpoints in human alcohol-related birth defects can be induced acutely in C57BL/6J mice during gastrulation-neurulation phases of development. Specific Aim 1 will survey the normal (developmental) gene expression for structures commonly malformed in alcohol-related birth defects. Parameterization will landmark key stages of ocular and hindbrain development across the window of vulnerability to ethanol-induced teratogenesis (days 8-10 of gestation) using C7BL/6J and CD-1 strains of mice that are differentially responsive to acute gestational exposure of ethanol. Conventional microdissection and laser capure microdissection will isolate specific precursor target cell populations from the test and reference samples. Specific Aim 2 will enumerate alcohol-related changes of gene expression within the exposure-disease continuum. Parameterization will entail dose-response, time after exposure, and strains differing in sensitivity. Emphasis will be the developing eye and hindbrain for exposure on day 9 of gestation. Specific Aim 3 is to initiate a functional genomics/computational biology pipeline for comprehensive pattern recognition, exploration, and validation of alcohol-related changes in developing target organs. Microarray data will be amalgamated into the first gene expression reference database for detecting alcohol-related effects on the developing embryo. This effort will enable computation of critical response signatures that represent core phenomena in disease mechanisms. By studying multigenic response signatures we hope to define the various metabolic and regulatory pathways set into disarray during critical periods of prenatal ethanol exposure. At ends, we expect this knowledge will enable researchers to identify mechanisms of alcohol-related birth defects and noninvasive strategies toward intervention. Project-generated resources will include the design and construction of specialized arrays focused on the genes emerging as responsive to ethanol intoxication, as well as a relational database made accessible to the scientific community through the world-wide web.