Brainstem Maturation in the Sudden Infant Death Syndrome

描述（由申请人提供）：婴儿猝死综合征（SIDS）是当今美国新生儿后期婴儿死亡的主要原因。在这项资助的支持下，已经连续资助了24年，我们报告了神经递质5-羟色胺（5-HT）及其生物合成酶，色氨酸羟化酶（TPH 2），在延髓的区域，调节心肺功能在睡眠（延髓5-HT系统）在四个独立的数据集的不足。这种缺陷也与5-HT受体、转运蛋白和细胞数量的异常有关。基于这些发现，我们提出SIDS是一种髓质5-HT系统中5-HT缺乏的疾病，其导致在危及生命的挑战后无法恢复稳态，例如，窒息，在睡眠期间，并导致突然死亡，在关键的第一年的生活时，稳态系统还没有完全成熟。在本周期中，我们进行了最先进的蛋白质组学鉴定候选蛋白质，这些蛋白质可以为SIDS中髓质5-HT缺乏的原因和发病机制提供新的见解。我们发现了几种蛋白质，这些蛋白质在SIDS病例和对照组之间的丰度显著不同，这些蛋白质以前从未被认为是SIDS脑干病理学的背景。这些蛋白质包括两个家族，我们选择在下一个周期进行研究，因为它们与5-HT神经传递直接相关：1）14-3-3蛋白，参与信号转导，包括TPH 2的调节;和2）某些突触蛋白，包括3-突触核蛋白，肌动蛋白和血影蛋白。我们的主要假设是，一个重要的子集SIDS是由于改变关键蛋白质有关的5-HT调节和突触传递在髓质5-HT系统。我们将分析在相同的情况下，以确定它们如何相互关联，并在正常的发展和小岛屿发展中国家使用免疫细胞化学，蛋白质印迹和其他组织技术的髓质5-HT系统的目标蛋白质。我们还将使用假设驱动的蛋白质组学来全面分析SIDS病例中5-HT突触通路上游的蛋白质和与对照组相比的14-3-3调控网络，以深入了解所观察到的蛋白质改变的潜在基础。拟议的研究有可能确定的基础上的髓质5-羟色胺缺乏症的SIDS的知识，这是必不可少的未来发展的一种手段，以确定和治疗活的婴儿的风险。

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.