Response Signatures of Alcohol-Related Birth Defects

酒精相关出生缺陷的反应特征

• 批准号: 6895693
• 负责人: Thomas B Knudsen
• 金额: $ 26.25万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-29 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6895693
• 关键词: alcoholism /alcohol abuse; congenital disorders; developmental genetics; embryo /fetus toxicology; ethanol; functional /structural genomics; gene expression; laboratory mouse; microarray technology; molecular biology information system

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.

胎儿酒精综合征（FAS）是指公认的先天缺陷模式，这些模式发生在怀孕期间食用酒精的妇女出生的子集中。 典型的酒精相关先天缺陷包括微型畸形，微观心脏，面部突出和内脏拱门的缺陷以及对心脏的影响，伟大的血管和胸腺。了解产前酒精暴露的疾病机制取决于了解哪种代谢和调节途径介导了导致畸形发生的关键步骤。 这里提出的研究使用基因表达阵列和生物信息学来探测急性动物模型中与酒精相关的先天缺陷的起源。 在发育的胃结束阶段，在C57BL/6J小鼠中，与人类酒精相关的出生缺陷中的许多疾病终点都可以诱导。 具体目标1将调查与酒精相关的先天缺陷中通常畸形的结构的正常（发育）基因表达。参数化将使用C7BL/6J和CD-1小鼠菌株对乙醇诱导的破坏的脆弱性（妊娠第8-10天）的脆弱窗口的关键阶段，这些阶段对乙醇的急性妊娠暴露有不同的反应。 常规的显微解剖和激光胶囊显微解剖会将特定的前体靶细胞群体与测试和参考样品分离。特定的目标2将列举与酒精相关的基因表达变化，在暴露酶连续体内。参数化将需要剂量反应，暴露后的时间和敏感性不同。 重点将是妊娠第9天暴露的眼睛和后脑。具体目的3是启动功能基因组学/计算生物学管道，以综合模式识别，探索和验证与酒精相关的靶心器官的变化。 微阵列数据将被合并到第一个基因表达参考数据库中，以检测与酒精相关的对发育中的胚胎的影响。 这项工作将实现代表疾病机制中核心现象的关键反应特征的计算。 通过研究多基因反应特征，我们希望在产前乙醇暴露的关键时期定义各种代谢和调节途径。 在目前，我们预计这些知识将使研究人员能够确定与酒精相关的先天缺陷和无创策略的机制。 项目生成的资源将包括专门针对乙醇中毒的基因的专业阵列的设计和构建，以及通过世界范围的网络可以访问科学界的关系数据库。