Brainstem Maturation in the Sudden Infant Death Syndrome

婴儿猝死综合症的脑干成熟

• 批准号: 8813600
• 负责人: ROBIN Lynn HAYNES
• 金额: $ 65.36万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-09-01 至 2017-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8813600
• 关键词: 14-3-3 Proteins; Actins; Anabolism; Apoptosis; Apoptotic; Arousal; Asphyxia; Autopsy; Binding; Brain Hypoxia-Ischemia; Brain Stem; Breathing; Cell Count; Cessation of life; Chemicals; Childhood; Chronic; Computers; Data Set; Development; Disease; Enzymes; Family; Funding; Future; Goals; Grant; Health; Homeostasis; Human; Infant; Infant Mortality; Intervention; JUN gene; Knowledge; Lead; Life; Live Birth; MAPK8 gene; Medulla Oblongata; Molecular; Neuroanatomy; Neurons; Neurotransmitters; Pathogenesis; Pathology; Pathway interactions; Phosphorylation; Phosphotransferases; Protein Isoforms; Proteins; Proteomics; Regulation; Reporting; Research; Risk; Risk Reduction; Serotonin; Signal Transduction; Site; Sleep; Spatial Distribution; Spectrin; Stress; Sudden Death; Sudden infant death syndrome; Synapses; Synaptic Transmission; Synaptosomes; System; TDO2 gene; Techniques; Testing; Tissues; Transcription Factor AP-1; Tryptophan 5-monooxygenase; United States; Western Blotting; base; case control; comparative; density; immunocytochemistry; insight; interest; neurotransmission; neurotransmitter release; novel; receptor; research study; synuclein

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.

描述（由申请人提供）：猝死综合征（SIDS）是当今美国杀害后婴儿死亡率的主要原因。在这笔赠款的主持下，已有24年的持续资助，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（TPH2）的缺乏，在延髓型心脏繁殖的区域（在四个数据室）中（dataull of Medull）在四处使用5-heles protive in Medull 5-dataull 5-hepry of dataull ford of dataull ford of dataull ford of dataull ford。这种缺乏也与5-HT受体，转运蛋白和细胞数的异常有关。根据这些发现，我们建议SIDS是髓质5-HT系统中5-HT缺乏症的疾病，这会导致在危及生命的挑战（例如窒息）中，在睡眠期间，导致体内的第一年，即体内稳态系统不完全成熟，无法恢复体内平衡。在目前的周期中，我们进行了最先进的蛋白质组学，以鉴定候选蛋白质，这些蛋白质可以为SIDS中髓质5-HT缺乏的原因和发病机理提供新的见解。我们发现了几种蛋白质在SIDS病例和对照组之间的丰度显着差异，而在SIDS脑干​​病理中从未考虑过。这些蛋白质包括我们选择在下一个周期中追求的两个家族，因为它们与5-HT神经传递直接相关：1）与信号转导有关的14-3-3蛋白，包括调节TPH2； 2）某些突触蛋白，包括3-核蛋白，肌动蛋白和光谱蛋白。我们过度骑行的假设是，小晶状体的一个重要子集是由于与5-HT调节和突触传播相关的关键蛋白质的改变引起的。我们将在相同情况下分析感兴趣的蛋白质，以确定它们如何相互融合，并使用免疫细胞化学，蛋白质印迹和其他组织技术在规范发展和SID中与髓质5-HT系统相互融合。与对照组相比，我们还将使用假设驱动的蛋白质组学在SIDS病例中全面分析5-HT突触途径上游的蛋白质和14-3-3的调节网络，以深入了解观察到的蛋白质改变的基础。拟议的研究有可能确定SIDS知识中髓质5-HT缺乏症的基础，这对于未来的发展是一种识别和治疗处于危险中的活生生的手段至关重要的。

项目成果

Arcuate nucleus hypoplasia in sudden infant death syndrome: a review.

婴儿猝死综合征中的弓形核发育不全：综述。

• DOI: 10.1159/000244045
• 发表时间: 1994
• 期刊: Biology of the neonate
• 作者: Filiano,JJ

Opioid receptors localize to the external granular cell layer of the developing human cerebellum.

阿片受体定位于发育中的人类小脑的外部颗粒细胞层。

• DOI: 10.1016/0306-4522(91)90099-a
• 发表时间: 1991
• 期刊: Neuroscience
• 影响因子: 3.3
• 作者: Kinney,HC;White,WF
• 通讯作者: White,WF

Developmental changes in [3H]lysergic acid diethylamide ([3H]LSD) binding to serotonin receptors in the human brainstem.

[3H]麦角酸二乙酰胺 ([3H]LSD) 与人脑干血清素受体结合的发育变化。

• DOI: 10.1097/00005072-199601000-00012
• 发表时间: 1996
• 期刊: Journal of neuropathology and experimental neurology
• 影响因子: 3.2
• 作者: Zec,N;Filiano,JJ;Panigrahy,A;White,WF;Kinney,HC
• 通讯作者: Kinney,HC

Three-dimensional distribution of [3H]quinuclidinyl benzilate binding to muscarinic cholinergic receptors in the developing human brainstem.

发育中的人脑干中与毒蕈碱胆碱能受体结合的[3H]苯苯甲酸奎宁环酯的三维分布。

• DOI: 10.1002/cne.903620305
• 发表时间: 1995
• 期刊: The Journal of comparative neurology.
• 作者: Kinney,HC;Panigrahy,A;Rava,LA;White,WF
• 通讯作者: White,WF

Decreased kainate receptor binding in the arcuate nucleus of the sudden infant death syndrome.

婴儿猝死综合征弓状核中红藻氨酸受体结合减少。

• DOI: 10.1097/00005072-199711000-00010
• 发表时间: 1997
• 期刊: Journal of neuropathology and experimental neurology
• 影响因子: 3.2
• 作者: Panigrahy,A;Filiano,JJ;Sleeper,LA;Mandell,F;Valdes-Dapena,M;Krous,HF;Rava,LA;White,WF;Kinney,HC
• 通讯作者: Kinney,HC