Fetal Brain Damage: A Placental Disorder

描述（由申请人提供） 翻译后摘要：胎盘长期以来一直被低估和研究不足的科学界。这一重要器官的功能不正常会导致胎儿畸形、早产和最常见的妊娠疾病先兆子痫。尽管胎盘很重要，但我们对其在胎儿发育中的作用的理解，特别是在分子水平上，是粗略的。可悲的是，我们对胎盘功能的理解可能与50年前对肾功能的认识相比较-我们可以描述解剖学，但不能描述生物学。我的首要目标是使用新的分子技术来了解胎盘功能及其与胎儿结局的关系。在这里，我的具体目标是调查胎盘激素如何塑造胎儿大脑发育。作为一个内分泌器官，胎盘产生大量的神经活性激素。这种内分泌功能可以通过多种方式被破坏-通过异常基因表达，感染，早产-导致长期损害。早产，影响所有分娩的十分之一，提供了激素损失的最极端情况，但我假设这只是胎盘功能障碍导致脑损伤的许多情况之一。我将培育一系列动物，在这些动物中，个别激素在发育过程中的精确时间从胎盘中专门去除。该系统将允许第一次直接，明确的测试胎盘作为胎儿大脑发育的关键调节器。既有激素，如孕激素和催产素，也有我们最近发现的由胎盘产生的神经调节剂，如促胰液素，都将被评估。这些实验可能会为胎盘生理学和神经发育提供基本的新见解，帮助重新定义脑瘫，自闭症和精神分裂症等疾病为胎盘疾病，并开辟新的治疗方法，以改善胎儿和婴儿的神经功能结果，具有高风险的发育性脑损伤。 公共卫生相关性：胎盘是健康妊娠的重要组成部分，胎盘功能受损与各种发育障碍有关，包括脑瘫，自闭症和精神分裂症。由于早产导致的胎盘激素的早期损失，每年影响美国超过40万名婴儿，以及由于先兆子痫或感染导致的胎盘功能不良，占全球妊娠相关死亡的大多数，可能是这些发育障碍的基础。了解胎盘激素在妊娠和大脑发育过程中的作用，正如本文提出的实验所研究的那样，可以提供新的治疗方法，可以改善早产儿和其他高风险发育性脑损伤的结果。

DESCRIPTION (Provided by the applicant) Abstract: The placenta has long been underappreciated and understudied by the scientific community. Improper function of this critical organ causes fetal abnormalities, premature labor and the most common disease of pregnancy, preeclampsia. Despite the importance of the placenta, our understanding of its role in fetal development, especially at a molecular level, is crude. Sadly, our understanding of placental function may be compared to the knowledge of kidney function 50 years ago-- we can describe the anatomy, but not the biology. My overarching goal is to use new molecular techniques to understand placental function and its relationship to fetal outcomes. Here my specific goal is to investigate how placental hormones shape fetal brain development. As an endocrine organ, the placenta produces a wide array of neuroactive hormones. This endocrine function can be disrupted in many ways- by abnormal gene expression, infection, prematurity- resulting in long-term damage. Preterm birth, affecting one tenth of all deliveries, provides the most extreme case of hormone loss, but I hypothesize that it is just one of many cases in which placental dysfunction leads to brain damage. I will develop a series of animals in which individual hormones are specifically removed from the placenta at precise times during development. This system will allow the first direct, definitive tests of the placenta as a key regulator of fetal brain development. Both established hormones, such as progestins and oxytocin, and hormones that we have recently identified as neuromodulators made by the placenta, such as secretin, will be assessed. These experiments are likely to provide fundamental new insights in placental physiology and neurodevelopment, help redefine disorders such as cerebral palsy, autism and schizophrenia as disorders of the placenta and open new avenues to theraputic treatments to improve neurological outcome in fetuses and infants at high risk of developmental brain damage. Public Health Relevance: The placenta is a vital component of healthy pregnancy and compromised placental function has been linked to diverse developmental disorders including cerebral palsy, autism and schizophrenia. The early loss of placental hormones due to preterm birth, which affects more than 400,000 infants in the United States each year, and poor placental function due to preeclampsia or infection, which accounts for the majority of pregnancy-related deaths worldwide, may underlie these developmental disorders. Understanding the role of placental hormones during pregnancy and brain development, as investigated by the experiments proposed here, can provide new approaches to treatments that can improve outcome in preterm infants and others at high risk of developmental brain damage.