Developmental Biology and Pathology Center

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（SIDS）的关系》（RFA：HD-03-004）的申请请求（RFA）的答复。我们小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，我们计划在受试者人群中开展与酒精相关的脑、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，产前暴露于酒精对脑干延髓中的多巴胺能（5-HT）系统的发育产生不利影响，从而使脆弱的胎儿/婴儿处于猝死的风险中，这是由于损害了一系列的稳态反射，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应激源，例如，缺氧高碳酸血症和低血压这一假设是我们对SIDS和对照病例的两个独立数据库进行脑干分析的直接结果，包括北方平原印第安人，这是一个高危人群。我们提出了5个具体目标的样本研究，以检查脑干5-HT和血管活性肠肽（VIP）之间的相互关系，后者在动物模型中的酒精诱导的损伤的发病机制中起着关键作用。在具体目标1中，我们将确定在胎儿和/或婴儿猝死谁暴露于产前酒精在延髓5-HT系统的异常是否与VIP异常在该系统中。在具体目标2中，我们将确定氧化应激标志物是否与这些胎儿/婴儿的髓质5-HT系统中的5-HT相关异常相关。在具体目标3中，我们提出了这样一个问题，即我们在SIDS婴儿中报告的相同脑干异常是否存在于原因不明的死胎中，这些数据将证实从胎儿期到婴儿期存在连续的疾病影响。在具体目标4中，我们试图了解5-HT相关标志物的多态性或突变是否与髓质5-HT系统异常和产前酒精暴露的胎儿/婴儿猝死风险增加相关。在具体目标5中，我们基于动物模型中酒精诱导的胎盘VIP减少的报道，解决了与胎盘中VIP表达相关的问题，胎盘是母胎体内平衡的关键器官。这些人类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治疗策略，以预防或改善产前酒精对发育中的人类大脑的损伤。

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.