Hormonal Programming and Epigenetic Imprinting in FAE

描述（由申请人提供）：本文提出的长期目标是阐明乙醇的表观遗传效应在胎儿酒精暴露后对抑郁和焦虑障碍的发育易感性中的作用。母亲乙醇消费是一个普遍存在的问题，本研究将对完成所提出的具体目标后的潜在逆转策略具有高度指导意义。其中包括测定乙醇介导的激素和脑和胎盘表观遗传变化的时间过程，以及实验分离乙醇诱导的母体甲状腺功能减退的表观遗传效应。我们还将确定乙醇改变印迹和甲状腺激素代谢的表观遗传机制，揭示未来逆转范式所针对的特定基因组区域。总之，获得的关于乙醇暴露的不同但相关的表观遗传和激素方面的信息将对乙醇在胎儿大脑中的作用的时间和性质有一个全面的了解。在我们能够实施有针对性的、定时的方法来逆转我们发现的每一种乙醇效应之前，由我们的数据生成的时间和生理轮廓是绝对必要的。我们高度重视该项目的健康相关性，因为它是基于适度但持续的胎儿酒精暴露水平。这一模式在母亲饮酒被接受或报告不足的人群中具有高度相关性，从而导致后代出现神经问题。这些缺陷在出生后发育和成年期间持续存在，造成贯穿整个生命周期的公共卫生问题。其中包括儿童学习障碍和多动症对教育系统的负面影响，以及随后成人精神疾病对社会、经济和卫生保健的相关影响。

DESCRIPTION (provided by applicant): The long-term goal of the thesis work proposed here is to elucidate the contribution of epigenetic effects of ethanol to the developmental susceptibility to depression and anxiety disorders seen after fetal alcohol exposure. Maternal ethanol consumption is a widespread problem and this research will be highly instructive as to potential reversal strategies after completion of the proposed specific aims. These include the determination of the time course of ethanol-mediated hormonal and epigenetic changes in the brain and placenta, and the experimental dissociation of epigenetic effects from the effects of ethanol-induced maternal hypothyroidism. We will also determine the epigenetic mechanism by which ethanol alters imprinting and thyroid hormone metabolism, unveiling the specific genomic regions that will be targeted by future reversal paradigms. Together, the information gained about the distinct but related epigenetic and hormonal aspects of ethanol exposure will create a comprehensive understanding of the timing and nature of ethanol's actions in the fetal brain. The temporal and physiological outline to be generated by our data is absolutely necessary before we can implement targeted, timed approaches to reverse each of the ethanol effects we uncover. We place high value on the health relevance of this project as it is based on a moderate but sustained level of fetal alcohol exposure. This paradigm is highly relevant in human populations in which maternal alcohol consumption is accepted or under-reported, resulting in neurological problems in the offspring. These deficits persist throughout postnatal development and adulthood, creating public health issues that manifest over the entire lifespan. These include negative effects on the education system attributable to childhood learning disabilities and hyperactivity, and subsequently, the social, financial, and health care-related repercussions of adult mental illness.