The Ventral Medulla and the Sudden Infant Death Syndrome

腹延髓和婴儿猝死综合症

• 批准号: 7931841
• 负责人: Hannah Chase Kinney
• 金额: $ 13.21万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7931841
• 关键词: Ventral; Medulla; Sudden; Infant; Death

DESCRIPTION (provided by applicant): Despite the success of the Back-to-Sleep campaign, the sudden infant death syndrome (SIDS) remains the leading cause of postneonatal infant mortality in the United States today. The major discovery of this program project in the last cycle was that multiple developmental abnormalities in the medullary serotonergic (5-HT) system are associated with SIDS. These human findings in Project 1 have lead to the establishment of a critical role for the medullary 5-HT system in the state-related regulation of multiple homeostatic functions in animal models in Projects 2-4. Additionally, they have lead to establishment of the developmental profile at the molecular level of the brainstem 5-HT system in Project 5. These discoveries have lead to the following over-riding hypothesis for the proposed third cycle: an important subset of SIDS is due to a developmental disorder of the medullary 5-HT system and related neuromodulator systems that are incurred prenatally, but which exerts its effects postnatally- during the first 6 months of life when the newborn, in transitioning to extrauterine life, undergoes maturation of circuitry for maintaining independent homeostasis and is at the greatest risk for SIDS. This disorder impairs protective homeostatic responses to potentially life-threatening, but often occurring, stressors during infant sleep that lead in turn to homeostatic derangements (hypoxia, hypercarbia), each potentially non-lethal in themselves, but which in combination precipitate death. Our objectives are: 1) To define the role of multiple transmitters/modulators in the neurochemical medullary pathology in SIDS infants; 2) To determine in rodent models the effect of homeostatic stressors-alone and in combination-upon autonomic and respiratory function during different sleep states, in males and females, and at different ages; 3) To determine the role of chronic intermittent hypoxia in the potentiation of the brainstem pathology in SIDS; 4) To determine the role of y-aminobutyric acid (GABA), orexin, substance P, norepinephrine, and acetylcholine in interacting with the medullary 5-HT system in homeostatic regulation in animal models; 5) To establish the organization and connectivity of the medullary 5-HT system-the "integrator" of diverse homeostatic functions mediated by multiple effector neurons; 6) To inhibit ("silence") molecularly defined subsets of 5-HT and GABA neurons and determine the physiological consequences in the living mouse. In the proposed third cycle, we will test the over-riding hypothesis utilizing a multidisciplinary approach in which human, animal, tissue slice, cell culture, and developmental data are integrated together, thereby informing and expanding upon each other towards establishing the pathogenesis of SIDS from the cellular to systems level. PROJECT 1: NEUROCHEMICAL PATHOLOGY IN SIDS BRAINSTEMS (Kinney, Hannah, M.D., pp 163-206) DESCRIPTION: The major discovery of Project 1 in the last cycle was that multiple abnormalities in the medullary serotonergic (5-HT) system are associated with SIDS. We now envision SIDS as a complex and heterogeneous process which involves multiple transmitters in addition to 5-HT, multiple stressors acting simultaneously, and multiple genetic and environmental factors, including chronic hypoxia and male gender, augmenting the brainstem defects. Our Specific Aims are: 1) To determine the neurochemical anatomy of Y-aminobutyric acid (GABA) in the medulla in SIDS cases. We will determine the number and density of GABA neurons, percent of 5-HT neurons that co-localize with GABA, GABAA receptor binding, and cellular localization of GABAA receptor subunits in SIDS cases compared with controls adjusted for age. 2) To determine the neurochemical anatomy of SP-expressing neurons and NK1 receptors in the medulla in SIDS cases. We will determine the number and density of SP neurons, the percent of 5-HT neurons that co-localize SP, SP binding, and cellular localization of NK1 in SIDS cases compared to controls adjusted for age. We will also determine if the SIDS cases with 5-HT1A and putative GABAA receptor binding abnormalities are the same as those with SP binding abnormalities. 3) To determine the role of estrogen and testosterone in the medullary pathology of SIDS. We will test the hypotheses that: androgen receptor binding is elevated in SIDS cases (male and female) in the medullary 5-HT system and/or its projection sites compared to controls adjusted for age; high serum testosterone levels correlate with high androgen binding in the same SIDS cases; and male SIDS cases with high serum testosterone levels have lower 5-HT1A receptor binding than SIDS infants with low serum testosterone levels and controls. 4) To determine the role of chronic intermittent hypoxia in the medullary pathology in SIDS and the role of compromised responses to hypoxia due to a defect in 5-HTmediated plasticity. We will test the hypothesis that SIDS cases show a reduced hypoxic response in the hypoglossal nucleus compared to hypoxic cases, as reflected in reduced hypoxic markers, e.g., erythropoietin. This hypothesis is based on the idea that hypoxic cases are equipped with a "normal" ability to respond to hypoxia, whereas the SIDS cases have an impaired ability. We will then test the hypothesis that markers of 5-HT-mediated plasticity to intermittent hypoxia (BDNF, TrkB receptors) are reduced in SIDS cases compared to hypoxic cases in the hypoglossal nucleus. This finding would suggest an inability of the SIDS infants to adapt to intermittent hypoxia due to 5-HT raphe-related abnormalities and impaired long-term facilitation. The proposed studies build upon an emerging picture of a complex brainstem phenotype in SIDS based upon a unique database accrued over 20 years in our laboratory.

描述（由申请人提供）：尽管背靠背运动取得了成功，但突然的婴儿死亡综合征（SIDS）仍然是当今美国昆虫后婴儿死亡率的主要原因。在最后一个周期中，该计划项目的主要发现是，髓质血清素能（5-HT）系统中的多种发育异常与SIDS相关。项目1中的这些人类发现导致在项目2-4中动物模型中多种体内稳态功能的髓质5-HT系统在与国家相关的多种稳态功能中的关键作用。此外，它们还导致在项目5中的脑干5-HT系统的分子水平上建立发展曲线。这些发现导致了提议的第三个周期的以下过度骑行假设：SIDS的一个重要子集是由于Medullary 5-HT系统和相关神经系统的临床效果，但其呈现的效果，该疾病是由于其在最初的效果而造成的，该疾病的生命是在此期间造成的，该疾病的生命是在其上呈现的。新生儿在过渡到额外生活时，经历了电路的成熟，以维持独立的体内平衡，并且对SIDS的风险最大。这种疾病会损害对潜在威胁生命的潜在稳态反应，但经常发生的婴儿睡眠期间的压力源反过来导致稳态危险（缺氧，高碳水化合物），每种疾病本身都可能非致死，但结合造成了死亡。我们的目标是：1）定义多个发射机/调节剂在小岛屿发展中心的神经化学病理学中的作用； 2）在啮齿动物模型中，在不同的睡眠状态，男性和女性以及不同年龄段的自主和呼吸功能中，稳态压力源和呼吸功能的组合的效果； 3）确定慢性间歇性缺氧在SIDS中脑干病理增强中的作用； 4）确定Y-氨基丁酸（GABA），Orexin，物质P，去甲肾上腺素和乙酰胆碱在动物模型中稳态调节中与髓质5-HT系统相互作用中的作用； 5）建立髓质5-HT系统的组织和连通性 - 多种效应神经元介导的各种稳态功能的“积分器”； 6）抑制5-HT和GABA神经元的分子定义的子集（“沉默”），并确定活小鼠的生理后果。在拟议的第三个周期中，我们将利用多学科的方法来测试人，动物，组织切片，细胞培养和发育数据的多学科方法，从而相互整合，从而相互告知和扩展，以确定从细胞到系统水平的SID的发病机理。 项目1：SIDS脑干​​中的神经化学病理学 （Kinney，Hannah，M.D.，第163-206页） 描述：最后一个周期中项目1的主要发现是髓质血清素能（5-HT）系统中的多个异常与SIDS相关。现在，我们将SIDS设想为一个复杂而异质的过程，除5-HT外，还涉及多个发射机，同时作用的多个压力源以及多个遗传和环境因素，包括慢性缺氧和男性性别，增强了脑干缺陷。我们的具体目的是：1）确定在SIDS病例中髓质中Y-氨基丁酸（GABA）的神经化学解剖学。我们将确定GABA神经元的数量和密度，与与年龄调整的对照组相比，SIDS病例中GABAA受体结合共定位的5-HT神经元中的GABAA受体结合和GABAA受体亚基的细胞定位。 2）确定在SIDS病例中髓质中SP表达神经元和NK1受体的神经化学解剖学。我们将确定SP神经元的数量和密度，即与对年龄调整的对照组相比，在SIDS病例中将SP，SP结合和细胞定位共定位的5-HT神经元百分比。我们还将确定患有5-HT1A和推定GABAA受体结合异常的SIDS病例是否与SP结合异常的情况相同。 3）确定雌激素和睾丸激素在SIDS的髓质病理学中的作用。我们将测试以下假设：与针对年龄调整的对照相比，在髓质5-HT系统和/或其投影位点的SIDS病例（男性和女性）中，雄激素受体结合升高；在相同的SIDS病例中，高血清睾丸激素水平与高雄激素结合相关；与血清睾丸激素水平低下的小岛屿发展中国家相比，血清睾丸激素水平高的男性小米小熊病例具有低5-HT1A受体结合。 4）确定慢性间歇性缺氧在SIDS中的髓质病理学中的作用，以及由于5-HTMDIDED塑性性缺陷而导致缺氧引起的对缺氧的反应的作用。我们将检验以下假设：与低氧病例相比，副核核中SIDS病例的低氧反应降低，如降低的低氧标记，例如促红细胞生成素。该假设是基于低氧病例具有对缺氧反应的“正常”能力的想法，而小岛屿发展中国家病例的能力受损。然后，我们将检验以下假设：与低脑核中低氧病例相比，在SIDS病例中，5-HT介导的可塑性对间歇性缺氧（BDNF，TRKB受体）的标记降低。这一发现表明，由于5-HT Raphe相关的异常和长期促进性，小岛屿发展中国家婴儿无法适应间歇性缺氧。拟议的研究基于在我们实验室中20年以上独特的数据库中，基于SIDS中复杂的脑干表型的新兴图片。