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.
