Fetal Alcohol Exposure and Sudden Infant Death Syndrome

我们实验室提供的证据表明，死于婴儿猝死综合征(SID)的婴儿中有很大一部分存在延髓5-羟色胺(5-HT)系统的异常，该系统负责调节多种体内平衡功能。小儿麻痹症的一个危险因素是怀孕前三个月期间母亲饮酒。我们推测，妊娠早期宫内酒精暴露会影响延髓5-羟色胺系统的发育和功能。孕期饮酒的小鼠模型将被用来解释以下假设：(1)5-羟色胺神经元的细胞和神经化学发育和功能；(2)通过抑制5-羟色胺特异的转录因子Pet-1和负责5-羟色胺前体发育的信号分子而影响5-羟色胺神经元的发育；以及(3)5-羟色胺神经元对高碳酸血症的化学接收功能 和缺氧。该项目的总体目标是了解胎儿酒精暴露作为婴儿猝死综合征的危险因素的基础，并最终制定治疗策略，以减轻与胎儿酒精暴露相关的不良影响。该项目将在波士顿儿童医院进行，可获得儿童医院以及哈佛社区周围医院的所有资源，包括一流的实验室设施、系列研讨会和继续教育。建议的项目将与涉及哈佛、达特茅斯和耶鲁的小岛屿发展中国家项目密切相关。这一基础设施将允许与作为该项目共同发起人的专家进行宝贵的合作。几乎所有方面都是如此 项目对候选人来说是新的，提供了学习多个新科学领域的机会。在这项工作的过程中，候选人将进步到独立，并为写RO1做准备。RO1将源于这笔赠款中提议的工作，因此，这项工作将是朝着建立一个由候选人担任首席调查员的实验室迈出的关键一步。

Our laboratory has provided evidence that a large proportion of infants dying of Sudden Infant Death Syndrome (SIDS) have abnormalities of the medullary serotonergic (5-HT) system, which is responsible for modulation of multiple homeostatic functions. A risk factor for SIDS is maternal alcohol consumption during the first trimester. We hypothesize that in utero exposure to alcohol during early gestation affects the development and function of the medullary 5-HT system. A mouse model of maternal alcohol consumption will be used to address the hypotheses that prenatal alcohol exposure affects the: (1) cellular and neurochemical development and functions of 5-HT neurons; (2) the development of 5-HT neurons through the suppression of 5-HT-specific transcription factor Pet-1 and the signaling molecules responsible for 5-HT precursor development; and (3) the chemoreception function of 5-HT neurons in response to hypercarbia and hypoxia. The overall goal of this project is to understand the basis of fetal alcohol exposure as a risk factor for SIDS, and to ultimately develop therapeutic strategies to alleviate the adverse effects associated with fetal alcohol exposure. The project will be done at Children's Hospital Boston with access to all resources from Children's, as well as surrounding hospitals in the Harvard community, including excellent laboratory facilities, seminar series, and continuing education. The project proposed will be done in close association with a program project on SIDS involving Harvard, Dartmouth, and Yale. This infrastructure will allow invaluable collaborations with experts who are co-sponsors of this project. Nearly all aspects of this project are new to the candidate, providing the opportunity to learn multiple new areas of science. Through the course of this work, the candidate will progress to independence, and prepare for writing an RO1. The RO1 will stem from work proposed in this grant, and thus, this work will be a critical step towards the establishment of a laboratory with the candidate as Principal Investigator.