The Hippocampus and Brainstem in the Sudden Infant Death Syndrome

婴儿猝死综合症中的海马和脑干

• 批准号: 10163061
• 负责人: ROBIN Lynn HAYNES
• 金额: $ 60.78万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-08 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10163061
• 关键词: 1 year old; 6 year old; Abnormal Cell; Age; Age-Months; Anatomy; Archives; Arousal; Autopsy; Back to Sleep; Biological Markers; Brain; Brain Stem; Cell Proliferation; Cessation of life; Chemicals; Child; Childhood; Chronic; Communities; Congenital Abnormality; Consensus; Data Set; Defect; Development; Disease; Epilepsy; Event; Formalin; Freezing; Gene Expression Profile; Genes; Genetic; Hippocampus (Brain); Incidence; Infant; Infant Mortality; Intervention; Investigation; Laboratories; Lesion; Life; Light Microscope; Live Birth; Low Birth Weight Infant; Maternal complication; Medical Examiners; Molecular; Mutation; Neurons; Parahippocampal Gyrus; Pathology; Patients; Pregnancy Complications; Reporting; Research; Risk; Role; Sclerosis; Seizures; Serotonin; Sleep; Subgroup; Sudden Death; Sudden infant death syndrome; System; Techniques; Temporal Lobe; Temporal Lobe Epilepsy; Testing; Tissues; United States; cell motility; cellular pathology; clinical phenotype; dentate gyrus; exome sequencing; granule cell; immunocytochemistry; infancy; infant death; laser capture microdissection; migration; molecular pathology; mossy fiber; neurochemistry; novel; postneonatal mortality; premature; response; success; transcriptomics

Project Summary Despite the safe sleep campaign, SIDS remains the leading cause of postneonatal infant mortality in the United States today, with an overall rate of 0.40/1000 live births. Our laboratory has provided compelling evidence in 4 independent datasets of defects in the serotonergic (5-HT) network in the medulla (lower brainstem) involved in protective responses to life-threatening challenges during sleep. These 5-HT defects include significantly decreased levels (~26%) of 5-HT itself in SIDS cases compared to age-adjusted controls. Over the last two decades, our group has provided substantial evidence, from studies using neurochemical techniques in frozen tissue, that a subset of SIDS is characterized by serotonergic (5-HT) brainstem pathology in regions involved in cardiorespiratory control and arousal. In 2015, we then reported a novel anatomic finding, from light microscope studies, in the dentate gyrus (DG) of the hippocampus in a major subgroup of SIDS cases (~40%) in a separate dataset. In this latter dataset, 5-HT brainstem neurochemical defects could not be simultaneously sought because the hippocampal tissues were from formalin fixed brains in the archives of the San Diego medical examiner's system. The dentate abnormality in SIDS is part of the spectrum of granule cell dispersion (GCD), which is characterized prominently by bilamination of the granule cells (GCs), so-called dentate bilamination (DB). DB and associated GC abnormalities in the SIDS cases had almost exclusively been reported previously in patients with temporal lobe epilepsy (TLE), some of who died from sudden unexplained death in epilepsy (SUDEP). We now ask: 1) Do cases of SIDS-DB also have 5-HT brainstem pathology? 2) Does the combined entity of SIDS-DB and 5-HT pathology share molecular, cellular, and genetic features with TLE and/or SUDEP? 3) Does SIDS-DB and 5-HT pathology represent one of many entities on a spectrum of underlying, intrinsic temporal lobe vulnerabilities associated with sudden death across life? In these scenarios, DB is postulated to be a developmental abnormality in GC proliferation and/or migration, and a precursor lesion to Ammon's horn sclerosis in TLE. We will test the overall hypothesis that the DG and medullary 5-HT network are both abnormal in the same SIDS cases, and that SIDS cases with DB share molecular, cellular, and genetic features in common with TLE and/or SUDEP. In four Specific Aims, we will test this hypothesis using a variety of state-of-the-art techniques, including transcriptomics with laser capture microdissection in the granule cells of the hippocampus, and whole exome sequencing in SIDS cases with DB. The study's potential impact is the discovery of a cause(s) of large subgroup (40%) of SIDS that will lead to intervention strategies, as well as biomarkers to identify living infants at risk. Understanding DB in SIDS also opens up avenues to elucidate the cellular and molecular pathology of sudden unexplained death beyond infancy, including SUDC and SUDEP.

项目摘要 尽管有安全的睡眠运动，但小岛屿发展中国家仍然是杀后婴儿死亡率的主要原因 今天的美国，总比例为0.40/1000个活产。我们的实验室提供了引人注目的 在髓质中的5-羟色胺能（5-HT）网络中的4个独立数据集中的证据（较低） 脑干）涉及对睡眠期间威胁生命的挑战的保护性反应。这些5-HT缺陷 与年龄调整后的对照相比，在SIDS病例中，包括5-HT本身的水平显着降低（约26％）。 在过去的二十年中，我们的小组通过使用神经化学的研究提供了大量证据 冷冻组织中的技术，一部分SIDs的特征是血清素能（5-HT）脑干病理学 在涉及心肺控制和唤醒的地区。在2015年，我们报告了一种新颖的解剖学 从光学显微镜研究中发现，在主要亚组的海马齿状回（DG）中 单独的数据集中的SIDS案例（〜40％）。在后一个数据集中，5-HT脑干神经化学缺陷可能 由于海马组织来自档案中的福尔马林固定大脑，因此不能同时寻求 圣地亚哥体检医师的系统。 SIDS中的齿状异常是频谱的一部分 颗粒细胞分散剂（GCD），通过颗粒细胞（GCS）的双层形式而显着特征 所谓的齿状双膜（DB）。 DB和相关的GC异常在SIDS案例中几乎具有 以前仅在颞叶癫痫患者（TLE）中报告，其中一些死于 癫痫突然无法解释的死亡（SUDEP）。我们现在问：1）sids-db的案例也有5-ht 脑干病理学？ 2）SIDS-DB和5-HT病理的联合实体共享分子， 细胞和遗传特征带有TLE和/或SUDEP？ 3）SIDS-DB和5-HT病理学代表 与基础，内在的颞叶脆弱性相关的许多实体之一 生命突然死亡？在这些情况下，DB被认为是 GC增殖和/或迁移，以及tle中Ammon Horn硬化症的前体病变。我们将测试 总体假设DG和髓质5-HT网络在相同的SIDS情况下都是异常的， 并且与DB共享分子，细胞和遗传特征的情况与TLE共有 和/或sudep。在四个具体目标中，我们将使用各种最先进的技术检验这一假设， 包括带有激光捕获海马颗粒细胞中的微解剖的转录组学，整个 在具有db的小岛屿文献中进行外显子组测序。该研究的潜在影响是发现的原因 大型亚组（40％）将导致干预策略以及生物标志物识别 有风险的活婴儿。了解小偷中的DB还开辟了途径，以阐明细胞和 超出婴儿期的突然无法解释的死亡的分子病理，包括SUDC和SUDEP。