Developmental Biology and Pathology Center

发育生物学和病理学中心

• 批准号: 6805210
• 负责人: HANNAH C KINNEY
• 金额: $ 42.77万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-26 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6805210
• 关键词: Native Americans; alcoholic beverage consumption; biomarker; clinical research; cooperative study; developmental neurobiology; embryo /fetus death; embryo /fetus toxicology; fetal alcohol syndrome; genetic polymorphism; health disparity; histopathology; homeostasis; human subject; immunocytochemistry; medulla oblongata; molecular pathology; oxidative stress; placenta; postmortem; serotonin; sudden infant death syndrome; teratogens; vasoactive intestinal peptide

DESCRIPTION (provided by applicant): This application is a response to the Request for Application (RFA) entitled: Prenatal Alcohol Exposure Among High-Risk Populations: Relationship to Sudden Infant Death Syndrome (SIDS) (RFA: HD-03-004). Our group is applying for the award of the Developmental Biology and Pathology Center. As requested in the RFA, we plan to conduct basic and applied research related to molecular and biological aspects of alcohol related injury to the brain, systemic organs, and placenta in the subject population. We hypothesize that prenatal exposure to alcohol adversely affects the development of the serotonergic (5-HT) system in the medulla oblongata of the brainstem, and thereby puts the vulnerable fetus/infant at risk for sudden death by compromising an array of homeostatic reflexes which are all influenced by the medullary 5-HT neurons, and which protect the fetus/infant from life-threatening stressors, e.g., hypoxia, hypercarbia, and hypotension. This hypothesis is a direct outgrowth of our brainstem analysis in two independent databases of SIDS and control cases, including in the Northern Plains Indians, a high-risk population. We propose 5 Specific Aims for the sample study to examine inter-relationships between brainstem 5-HT and vasoactive intestinal peptide (VIP), the latter shown to play a pivotal role in the pathogenesis of alcohol-induced injury in animal models. In Specific Aim 1 we will determine if abnormalities in the medullary 5-HT system correlate with VIP abnormalities in this system in fetuses and/or infants with sudden death who were exposed to prenatal alcohol. In Specific Aim 2, we will determine if markers of oxidative stress correlate with5-HT-related abnormalities in the medullary 5-HT system in such fetuses/infants. In Specific Aim 3, we address the question if the same brainstem abnormalities reported by us in SIDS infants are present in unexplained stillbirth, data which would substantiate the idea that there is a continuum of disease-effect from the fetal period through infancy. In Specific Aim 4, we seek to know if polymorphisms or mutations in 5-HT-related markers are associated with medullary 5-HT system abnormalities and an increased risk for sudden death in fetuses/infants exposed to prenatal alcohol. In Specific Aim 5, we address issues related to VIP expression in the placenta, the key organ of maternal-fetal homeostasis, based upon reports of alcohol-induced reductions in placental VIP in animal models. These human studies should help provide the necessary critical steps to translate basic science findings into therapeutic strategies for the prevention or amelioration of prenatal alcohol-induced injury to the developing human brain.

描述(由申请人提供)：本申请是对题为：高危人群产前酒精暴露：与婴儿猝死综合征的关系的申请的回应(RFA：HD-03-004)。我们小组正在申请发育生物学和病理学中心的奖项。按照RFA的要求，我们计划在受试者群体中开展与酒精对大脑、全身器官和胎盘造成的损伤的分子和生物学方面相关的基础和应用研究。我们假设，产前接触酒精会对脑干延髓5-羟色胺(5-HT)系统的发育产生不利影响，从而使脆弱的胎儿/婴儿面临猝死的风险，因为这些反应都受到延髓5-羟色胺神经元的影响，并保护胎儿/婴儿免受威胁生命的应激因素的影响，如缺氧、高碳酸血症和低血压。这一假设是我们在两个独立的小岛屿发展中国家和对照病例数据库中进行脑干分析的直接结果，其中包括北部平原印第安人，这是一个高危人群。我们提出了5个特定的样本研究目标，以考察脑干5-羟色胺和血管活性肠肽(VIP)之间的相互关系，后者被证明在酒精性损伤动物模型的发病机制中发挥关键作用。在特定的目标1，我们将确定延髓5-羟色胺系统的异常是否与胎儿期酒精暴露的胎儿和/或猝死婴儿的5-羟色胺系统VIP异常相关。在特定的目标2中，我们将确定氧化应激的标志物是否与此类胎儿/婴儿的髓质5-羟色胺系统中5-羟色胺相关的异常有关。在具体目标3中，我们解决了我们在小岛屿发展中国家婴儿中报告的相同脑干异常是否存在于无法解释的死产中的问题，这些数据将证实从胎儿时期到婴儿时期存在一系列疾病影响的想法。在具体目标4中，我们试图了解5-羟色胺相关标志物的多态或突变是否与延髓5-羟色胺系统异常和胎儿/婴儿暴露于产前酒精中猝死风险增加有关。在特定的目标5中，我们基于动物模型中酒精诱导的胎盘VIP减少的报道，解决了与胎盘VIP表达相关的问题，胎盘是母胎动态平衡的关键器官。这些人体研究应该有助于提供必要的关键步骤，将基础科学发现转化为治疗策略，以预防或改善产前酒精对发育中的人脑造成的损伤。