Fetal Alcohol Exposure and Sudden Infant Death Syndrome

我们的实验室提供的证据表明，大部分死于婴儿猝死综合症 (SIDS) 的婴儿都存在髓质血清素 (5-HT) 系统异常，该系统负责调节多种稳态功能。 SIDS 的一个危险因素是孕早期母亲饮酒。我们假设妊娠早期在子宫内接触酒精会影响髓质 5-HT 系统的发育和功能。母亲饮酒的小鼠模型将用于解决产前酒精暴露影响以下假设：(1) 5-HT 神经元的细胞和神经化学发育和功能； (2)通过抑制5-HT特异性转录因子Pet-1和负责5-HT前体发育的信号分子来发育5-HT神经元； (3) 5-HT神经元对高碳酸血症的化学感受功能 和缺氧。该项目的总体目标是了解胎儿酒精暴露作为 SIDS 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利影响。该项目将在波士顿儿童医院进行，可以使用儿童医院以及哈佛社区周边医院的所有资源，包括优良的实验室设施、研讨会系列和继续教育。拟议的项目将与哈佛、达特茅斯和耶鲁大学参与的小岛屿发展中国家计划项目密切相关。该基础设施将允许与该项目共同发起人的专家进行宝贵的合作。几乎涉及到这一切的各个方面 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。通过这项工作的过程，候选人将取得独立性，并为撰写 RO1 做好准备。 RO1 将源于本次资助中提出的工作，因此，这项工作将是建立一个由候选人作为首席研究员的实验室的关键一步。

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.