BRAINSTEM MATURATION IN THE SUDDEN INFANT DEATH SYNDROME

婴儿猝死综合症(SEDS)是新生儿后死亡的主要原因，总体上 活产儿发病率为0.8/1000。其原因(S)不明。基于我们对小岛屿发展中国家患者的脑干研究 在上一个资助周期，我们提出了一个关于延髓腹侧的作用的扩展假说，这一区域与 化学感受，自主神经反应，呼吸驱动，体温调节，以及神经递质，5-羟色胺(5- 在小儿麻痹症的发病机制中：小儿麻痹症，或小儿麻痹症的一个子集，是由于腹侧发育异常引起的 由菱形唇源性5-羟色胺能神经元组成的延髓网络，这种异常导致 对威胁生命的挑战(如窒息、缺氧、高碳酸血症)的保护性反应失败 睡眠，在特定的目标1-3中，我们将描述5-羟色胺延髓腹侧网络的正常发育 脑组织横跨生命早期，是SIDS发病的时间段。我们将利用选定的标记来检测5-羟色胺 细胞，终末，受体亚型，以及合成酶，色氨酸羟基酶，使用组织放射自显影， 人类胚胎、胎儿和婴儿脑组织的免疫细胞化学和原位杂交。我们会 然后确定与年龄匹配的对照组相比，SIDS患者的5-羟色胺发育是如何异常的。 5-羟色胺标志物。在特定的目标4中，我们将确定哪些细胞群体来自人类的菱形嘴唇 转录因子的细胞和分子标记在动物研究中与菱形唇形衍生有关，我们 将确定小岛屿发展中国家患者腹侧延髓网络中受影响的核是否来自同一胚胎 安拉奇。我们将确定是否存在神经元和反应性星形胶质细胞(胶质增生)的异常数量 小岛屿发展中国家患者的菱形唇形核。我们预测，我们不会在这些细胞核中发现胶质增生(疤痕)， 表明是发育缺陷，而不是退化缺陷。建议的研究应该：证实5-羟色胺缺陷 在小岛屿发展中国家患者的腹侧延髓中；提供对正常发育以及分子和化学的洞察 人类5-羟色胺腹侧延髓网络的解剖学研究；并提示小儿麻痹症患者功能异常的线索。 在动物模型中进行测试，以及在人类婴儿中设计具体的预防策略和诊断测试。

The sudden infant death syndrome (SEDS) is the leading cause of postneonatal infant mortality, with an overall incidence of 0.8/1000 live births. Its cause(s) is unknown. Based upon our brainstem studies in SIDS victims during the last grant cycle, we propose an expanded hypothesis concerning the role of the ventral medulla, a region related to chemoreception, autonomic responses, respiratory drive, and thermoregulation, and the neurotransmitter, serotonin (5- HT) in the pathogenesis of SIDS: SIDS, or a subset of SIDS, is due to a developmental abnormality in a ventral medullary network composed of rhombic lip-derived, serotonergic neurons, and this abnormality results in a failure of protective responses to life-threatening challenges (e.g., asphyxia, hypoxia, hypercapnia) during sleep, hi Specific Aims 1-3, we will characterize the normal development of the 5-HT ventral medullary network in brain tissues across early life, the time-period of the pathogenesis of SIDS. We will utilize selected markers to 5-HT cells, terminals, receptor subtypes, and the synthetic enzyme, tryptophan hydroxylase, using tissue autoradiography, immunocytochemistry, and in situ hybridization in brain tissues from human embryos, fetuses, and infants. We will then determine how 5-HT development is abnormal in SIDS victims compared to age-matched controls with the same. 5-HT markers. In Specific Aim 4, we will establish which cell populations derive from the human rhombic lip using cellular and molecular markers to transcription factors implicated in rhombic lip-derivation in animal studies, and we will determine if the affected nuclei in the ventral medullary network in SIDS victims derive from this same embryonic anlage. We will determine if there is an abnormal number of neurons and reactive astrocytes (gliosis) in selected rhombic lip-derived nuclei in SIDS victims. We predict that we will not find gliosis (scarring) in these nuclei, suggesting a developmental, rather than degenerative, defect. Theproposed studies should: substantiate a 5-HT defect in the ventral medulla of SIDS victims; provide insight into the normal development and the molecular and chemical anatomy of the human 5-HT ventral medullary network; and suggest clues about abnormal function in SIDS victims for testing in animal models, and for devising specific preventive strategies and diagnostic tests in human infants.