Response Signatures of Alcohol-Related Birth Defects

胎儿酒精综合征（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儿童中。 典型的与酒精有关的出生缺陷包括小脑畸形、小眼畸形、面部神经和内脏弓缺陷，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哪些代谢和调节途径介导导致畸形的关键步骤。 本文提出的研究使用基因表达阵列和生物信息学在急性动物模型中探索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以在C57 BL/6 J小鼠的原肠胚-神经胚发育阶段急性诱导。 具体目标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。使用对急性妊娠期乙醇暴露有差异反应的C7 BL/6 J和CD-1小鼠品系，参数化将标志眼和后脑发育的关键阶段，跨越乙醇诱导致畸作用的脆弱性窗口（妊娠第8-10天）。 常规显微切割和激光捕获显微切割将从供试品和参比品中分离出特定的前体靶细胞群。具体目标2将列举酒精相关的基因表达的变化，在糖尿病连续体。参数化将需要剂量反应，暴露后的时间，以及敏感性不同的菌株。 重点将是妊娠第9天暴露的发育中的眼睛和后脑。具体目标3是启动功能基因组学/计算生物学管道，用于全面模式识别、探索和验证发育中目标器官中与酒精相关的变化。 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胚胎的影响。 这一努力将能够计算代表疾病机制中核心现象的关键反应特征。 通过研究多基因反应信号，我们希望能够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，我们希望这些知识将使研究人员能够确定酒精相关的出生缺陷和非侵入性干预策略的机制。 项目产生的资源将包括设计和建造专门的阵列，重点是对乙醇中毒有反应的基因，以及通过万维网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.