Molecular Mechanisms of Alcohol Related Birth Defects

酒精相关出生缺陷的分子机制

• 批准号: 7086998
• 负责人: Shao-yu Chen
• 金额: $ 11.86万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7086998
• 关键词: apoptosis; confocal scanning microscopy; congenital disorders; developmental neurobiology; embryo /fetus culture; embryo /fetus drug adverse effect; ethanol; eye; gene expression; high performance liquid chromatography; in situ hybridization; laboratory mouse; laboratory rat; labyrinth; laser capture microdissection; microarray technology; neurogenetics; retinoids; scanning electron microscopy; teratogens; terminal nick end labeling

DESCRIPTION (provided by applicant): The proposed plan is designed to secure advanced training for my career development and allow me to become an independent investigator in a dynamic alcohol research environment. These career goals constitute steps in my more comprehensive plan to one day apply for a tenure track position, further solidify my research program and complete my transition to independent research status. To meet the career development goals, a systematic plan has been developed which include course work, workshops, interaction with my mentors and consultant, attending professional meetings, seminars and conferences, research training and grant application writing. The proposed research project is designed to increase our understanding of the molecular mechanisms underlying alcohol-induced dysmorphogenesis. It follows up on our previous identification of selected regions of the brain, otic, and optic primordia as targets of ethanol induced apoptosis and subsequent birth defects. Using in situ hybridization, we will test the hypothesis that abnormal expression of patterning genes occurs in the embryonic brain, eye and inner ear shortly after ethanol exposure; changes that presage subsequent dysmorphogenesis. Analyses of temporally and regionally-specific alterations in patterning genes and apoptosis will be conducted utilizing an acute ethanol exposure paradigm, whole embryo culture, and laser confocal imaging. Recognizing that ethanol exposure can interfere with retinoid metabolism and that retinoic acid regulates gene expression, we will also examine the hypothesis that diminishing retinoic acid-dependent gene signaling underlies ethanol's teratogenicity. For this work, we will compare gene expression patterns and patterns of apoptosis in the developing brain, eye and inner ear of retinoid-deficient (BMS493-treated) and ethanol-exposed mouse embryos and test retinoic acid's ameliorative potential. Additionally, because complex adaptive responses almost certainly are multigenic, we will identify and classify gene networks and pathways that mediate critical events in the ethanol-exposed developing brain using microarray-based analysis. Specifically, the gene networks and pathways that underlie the ethanol's concentration-dependent effects in the embryonic mouse brain will be identified and compared. This study is expected to provide important new data relative to molecular mechanisms of alcohol-related birth defects.

描述（由申请人提供）： 拟议的计划旨在确保我的职业发展的高级培训，让我成为一个动态的酒精研究环境中的独立调查员。这些职业目标构成了我更全面的计划中的步骤，以便有一天申请终身职位，进一步巩固我的研究计划，并完成我向独立研究身份的过渡。为了实现职业发展目标，我制定了一个系统的计划，其中包括课程工作，研讨会，与我的导师和顾问互动，参加专业会议，研讨会和会议，研究培训和赠款申请写作。拟议的研究项目旨在增加我们对酒精诱导的畸形形成的分子机制的理解。它跟进我们以前的识别选定区域的大脑，耳，视神经原基乙醇诱导的细胞凋亡和随后的出生缺陷的目标。使用原位杂交，我们将测试的假设，即异常表达的图案基因发生在胚胎的大脑，眼睛和内耳后不久，乙醇暴露，变化预示着随后的畸形。将利用急性乙醇暴露范例、全胚胎培养和激光共聚焦成像对图案化基因和细胞凋亡的时间和区域特异性改变进行分析。认识到乙醇暴露可以干扰类维生素A代谢和视黄酸调节基因表达，我们还将研究假设，减少视黄酸依赖性基因信号的基础乙醇的致畸性。在这项工作中，我们将比较基因表达模式和细胞凋亡的模式在发育中的大脑，眼睛和内耳的维甲酸缺乏（BMS493处理）和乙醇暴露的小鼠胚胎和测试维甲酸的改善潜力。此外，由于复杂的适应性反应几乎肯定是多基因的，我们将使用基于微阵列的分析来识别和分类在乙醇暴露的发育中的大脑中介导关键事件的基因网络和途径。具体来说，基因网络和途径，乙醇的浓度依赖性影响的胚胎小鼠大脑的基础将被确定和比较。这项研究有望为酒精相关出生缺陷的分子机制提供重要的新数据。