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.

描述（由申请人提供）：此申请是对申请请求（RFA）的响应：高风险人群中的产前酒精暴露：与猝死综合征（SIDS）的关系（RFA：HD-03-004）。我们的小组正在申请发育生物学和病理中心的奖励。按照RFA的要求，我们计划进行与大脑相关损伤的分子和生物学方面有关的基本和应用研究，对大脑，系统性器官和受试者人群中的胎盘。我们假设，产前暴露于酒精会对脑干的髓质长方体中的血清素能（5-HT）系统的发展产生影响，从而使脆弱的胎儿/婴儿遭受猝死的风险，因损害了一系列的体内平衡反映，这些反射都受到髓质的影响。例如，缺氧，高碳酸盐和低血压。该假设是我们脑干分析的直接产生，在两个独立的小岛屿发展中国家数据库和控制案例的数据库中，包括在北平原印第安人，高风险人群中。我们提出了5个特定目的，用于样本研究检查脑干5-HT与血管活性肠肽（VIP）之间的相互关系，后者在动物模型中证明在酒精诱导的损伤的发病机理中起着关键作用。在特定的目标1中，我们将确定髓质5-HT系统中的异常是否与该系统中的VIP异常相关，在胎儿和/或猝死的婴儿中暴露于产前酒精。在特定的目标2中，我们将确定在这种胎儿/婴儿中，氧化应激标记是否与髓质5-HT系统中5-HT相关的异常相关。在特定的目标3中，我们解决了一个问题，如果我们在少年婴儿中报告了我们在SIDS婴儿中报道的相同的脑干异常，这将证明从胎儿到婴儿期从胎儿期开始存在疾病效应的观念。在特定的目标4中，我们试图知道5-HT相关标记中的多态性或突变是否与髓质5-HT系统异常有关，并且暴露于产前酒精的胎儿/婴儿突然死亡的风险增加。在特定的目标5中，我们基于胎盘的胎盘表达（胎盘稳态的关键器官）的VIP表达问题，该问题是基于酒精引起的动物模型中胎盘VIP降低的报道。这些人类研究应有助于提供必要的关键步骤，以将基础科学发现转化为预防或改善产前酒精引起的人脑损伤的治疗策略。