Brainstem Maturation in the Sudden Infant Death Syndrome

描述(申请人提供)：婴儿猝死综合症(SIDS)是当今美国新生儿后死亡的主要原因。在这项持续资助了24年的赠款的支持下，我们在四个独立的数据集中报告了延髓中调节睡眠期间心肺功能的区域(延髓5-羟色胺系统)的神经递质5-羟色胺(5-HT)及其生物合成酶色氨酸羟基酶(TPH2)的缺乏。这种缺陷还与5-羟色胺受体、转运体和细胞数量的异常有关。基于这些发现，我们认为SIDS是延髓5-羟色胺系统中5-羟色胺缺乏的紊乱，导致在睡眠期间面临威胁生命的挑战(如窒息)后无法恢复内稳态，并导致在生命关键的第一年内稳态系统尚未完全成熟时猝死。在本周期中，我们应用最先进的蛋白质组学技术来确定候选蛋白质，这可能为了解小岛屿发展中国家5-羟色胺缺乏症的病因(S)和发病机制提供新的见解。我们发现，在小岛屿发展中国家病例和对照中，有几种蛋白质的丰度存在显著差异，这些蛋白质以前从未在小岛屿发展中国家脑干病理学的背景下被考虑过。这些蛋白包括两个我们选择在下一个周期中研究的蛋白家族，因为它们与5-羟色胺神经传递直接相关：1)参与信号转导的14-3-3蛋白，包括TPH2的调节；2)某些突触蛋白，包括3-突触核蛋白、肌动蛋白和血影蛋白。我们的假设是，SID的一个重要子集是由于与5-羟色胺调节和延髓5-羟色胺系统突触传递相关的关键蛋白的改变。我们将利用免疫细胞化学、免疫印迹和其他组织技术分析相同病例中感兴趣的蛋白质，以确定它们是如何相互关联的，以及它们如何与正常发育和SID中的髓质5-羟色胺系统相关。我们还将使用假说驱动的蛋白质组学来全面分析5-羟色胺突触通路上游的蛋白质和14-3-3调控网络，并与对照组进行比较，以深入了解观察到的蛋白质变化的潜在基础。这项拟议的研究有可能确定小岛屿发展中国家5-羟色胺缺乏症的潜在基础--这一知识对于未来开发一种识别和治疗处于危险中的活婴儿的方法至关重要。 与公共卫生相关：婴儿猝死综合症(SIDS)是当今美国新生儿后婴儿死亡的首要原因，也是导致整个婴儿死亡的第三大原因。我们的研究表明，大多数SID病例与脑干区域神经递质5-羟色胺缺乏有关，这种神经递质影响睡眠期间的呼吸和自主神经功能。我们的目标是通过人类脑干分析中最先进的技术来确定这一缺陷的根本基础。这些知识对于今后开发一种识别和治疗处于危险中的活体婴儿的手段至关重要。

DESCRIPTION (provided by applicant): The sudden infant death syndrome (SIDS) is the leading cause of postneonatal infant mortality in the United States today. Under the auspices of this grant which has been continuously funded for 24 years, we have reported a deficiency of the neurotransmitter serotonin (5-HT) and its biosynthetic enzyme, tryptophan hydroxylase (TPH2), in regions of the medulla oblongata that modulate cardiorespiratory function during sleep (the medullary 5-HT system) in four independent datasets. This deficiency is also associated with abnormalities in 5-HT receptors, transporter, and cell number. Based upon these findings, we propose that SIDS is a disorder of 5-HT deficiency in the medullary 5-HT system which causes an inability to restore homeostasis following life-threatening challenges, e.g., asphyxia, during a sleep period and leads to sudden death in the critical first year of life when homeostatic systems are not fully mature. In the present cycle, we performed state-of-the-art proteomics to identify candidate proteins which could provide novel insight into the cause(s) and pathogenesis of the medullary 5-HT deficiency in SIDS. We discovered several proteins that differed significantly in abundance between the SIDS cases and controls that have never before been considered in the context of SIDS brainstem pathology. These proteins include two families that we have chosen to pursue in the next cycle because they are directly relevant to 5-HT neurotransmission: 1) 14-3-3 proteins which are involved in signal transduction, including in regulation of TPH2; and 2) certain synaptic proteins, including 3-synuclein, actin, and spectrin. Our over-riding hypothesis is that an important subset of SIDS is due to alterations in key proteins related to 5-HT regulation and synaptic transmission in the medullary 5-HT system. We will analyze the proteins of interest in the same cases in order to determine how they inter-relate to each other and to the medullary 5-HT system in normative development and SIDS using immunocytochemical, western blotting, and other tissue techniques. We will also use hypothesis-driven proteomics to analyze comprehensively proteins upstream of 5-HT synaptic pathways and the 14-3-3 regulatory network in SIDS cases compared to controls to gain insight into the underlying basis of the observed protein alterations. The proposed study has the potential to determine the underlying basis of the medullary 5-HT deficiency in SIDS-knowledge which is essential to the future development of a means to identify and treat living infants at risk. PUBLIC HEALTH RELEVANCE: The sudden infant death syndrome (SIDS) is the leading cause of postneonatal infant mortality and the third leading cause of infant mortality overall in the United States today. Our research suggests that the majority of SIDS cases is associated with a deficiency of the neurotransmitter serotonin in brainstem regions that influence breathing and autonomic function during sleep. Our goal is to determine the fundamental basis of this deficiency by state-of-the-art techniques in human brainstem analysis. Such knowledge is essential to the future development of a means to identify and treat living infants at risk.