Developmental Biology and Pathology Center

发育生物学和病理学中心

• 批准号: 6928598
• 负责人: HANNAH C KINNEY
• 金额: $ 43.9万
• 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/6928598
• 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.

说明（由申请人提供）：本申请是对标题为：高危人群产前酒精暴露：与婴儿猝死综合症 (SIDS) 的关系 (RFA：HD-03-004) 的申请请求 (RFA) 的回应。我们课题组正在申请发育生物学和病理学中心的奖项。根据 RFA 的要求，我们计划开展与酒精相关的大脑、全身器官和胎盘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中的血清素（5-HT）系统的发育产生不利影响，从而通过损害一系列稳态反射而使脆弱的胎儿/婴儿面临猝死的风险，这些反射都受到延髓5-HT神经元的影响，并保护胎儿/婴儿免受危及生命的压力源的影响， 例如，缺氧、高碳酸血症和低血压。这一假设是我们对两个独立的 SIDS 和对照病例数据库进行脑干分析的直接结果，其中包括高危人群北部平原印第安人。我们为样本研究提出了 5 个具体目标，以检查脑干 5-HT 和血管活性肠肽 (VIP) 之间的相互关系，后者在动物模型中酒精引起的损伤的发病机制中发挥着关键作用。在具体目标 1 中，我们将确定暴露于产前酒精的胎儿和/或猝死婴儿的髓质 5-HT 系统异常是否与该系统的 VIP 异常相关。在具体目标 2 中，我们将确定氧化应激标志物是否与此类胎儿/婴儿髓质 5-HT 系统中 5-HT 相关异常相关。在具体目标 3 中，我们解决了我们在 SIDS 婴儿中报告的相同脑干异常是否也存在于不明原因死产中的问题，这些数据将证实从胎儿期到婴儿期存在连续的疾病影响这一观点。在具体目标 4 中，我们试图了解 5-HT 相关标记物的多态性或突变是否与髓质 5-HT 系统异常以及暴露于产前酒精的胎儿/婴儿猝死风险增加相关。在具体目标 5 中，我们根据动物模型中酒精诱导的胎盘 VIP 减少的报告，解决了与胎盘（母胎稳态的关键器官）中 VIP 表达相关的问题。这些人体研究应有助于提供必要的关键步骤，将基础科学发现转化为预防或改善产前酒精对发育中的人类大脑造成的损伤的治疗策略。