Brainstem Maturation in the Sudden Infant Death Syndrome

婴儿猝死综合症的脑干成熟

基本信息

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
项目类别：
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

项目摘要

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.

描述（由申请人提供）：婴儿猝死综合症（SIDS）是当今美国新生儿后婴儿死亡的主要原因。在这项已连续资助 24 年的资助下，我们报告了调节心肺功能的延髓区域神经递质血清素 (5-HT) 及其生物合成酶色氨酸羟化酶 (TPH2) 的缺乏睡眠期间（髓质 5-HT 系统）的四个独立数据集。这种缺陷还与 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，导致在睡眠期间面临危及生命的挑战（例如窒息）后无法恢复体内平衡，并导致猝死在生命关键的第一年，体内平衡系统尚未完全成熟。在本周期中，我们进行了最先进的蛋白质组学来鉴定候选蛋白质，这些蛋白质可以为 SIDS 髓质 5-HT 缺乏的原因和发病机制提供新的见解。我们发现了几种在 SIDS 病例和对照之间丰度显着差异的蛋白质，这些蛋白质以前从未在 SIDS 脑干病理学背景下被考虑过。这些蛋白质包括我们选择在下一个周期中研究的两个家族，因为它们与 5-HT 神经传递直接相关：1) 14-3-3 蛋白质，参与信号转导，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。我们最重要的假设是，SIDS 的一个重要子集是由于与髓质 5-HT 系统中 5-HT 调节和突触传递相关的关键蛋白质的改变所致。我们将使用免疫细胞化学、蛋白质印迹和其他组织技术分析相同病例中的目标蛋白，以确定它们在规范发育和 SIDS 中如何相互关联以及与髓质 5-HT 系统之间的相互关系。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 14-3-3 调节网络，与对照组进行比较，以深入了解观察到的蛋白质变化的根本基础。拟议的研究有可能确定 SIDS 知识中髓质 5-HT 缺乏的根本原因，这对于未来开发识别和治疗处于危险中的活婴儿的方法至关重要。

项目成果

期刊论文数量（48）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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
影响因子：
0
作者：
Filiano,JJ
通讯作者：
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

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

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。