Fetal Alcohol Exposure and Sudden Infant Death Syndrome

我们的实验室提供的证据表明，很大一部分死于婴儿猝死综合征（SIDS）的婴儿有异常的髓质肾上腺素能（5-HT）系统，这是负责多种稳态功能的调制。婴儿猝死综合征的一个危险因素是母亲在怀孕的头三个月饮酒。我们推测，在子宫内暴露于酒精在妊娠早期影响的发展和功能的髓质5-羟色胺系统。母亲饮酒的小鼠模型将被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影响5-HT神经元的发育;（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风险因素的基础，并最终制定治疗策略以减轻与胎儿酒精暴露相关的不良反应。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围医院的所有资源，包括优秀的实验室设施、系列研讨会和继续教育。拟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方案项目密切联系进行。这一基础设施将允许与该项目的共同发起人专家进行宝贵的合作。几乎所有的方面 项目是新的候选人，提供学习科学的多个新领域的机会。通过这项工作的过程中，候选人将进步到独立，并准备写一个RO 1。RO 1将源于本补助金中提出的工作，因此，这项工作将是建立实验室的关键一步，候选人将担任主要研究员。

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.