Early Placental Development in IUGR Pregnancies

描述（由申请人提供）：婴儿宫内生长受限（IUGR）是婴儿死亡和发病的主要原因。此外，过去十年的研究提供了令人信服的证据，表明IUGR婴儿成年后冠心病、2型糖尿病、高血压和中风的发病率更高。大多数IUGR病例是由胎盘功能不全（PI）引起的，我们的目标是了解PI-IUGR的潜在机制，并制定干预方法。绵羊PI-IUGR具有人类IUGR妊娠的许多生理生化特征，我们利用绵羊PI-IUGR自然模型，观察到随着IUGR妊娠的发展，胎盘基因表达的急性和慢性变化。目前，我们的目标是确定导致PI-IUGR的胎盘发育改变的机制，重点关注胎盘发育的急性变化。计划3个具体目的：1)确定子宫血流和摄氧量是否在胎盘功能不全的发展过程中发生急剧改变；2)研究IUGR胎盘内细胞反应导致血管内皮生长因子表达增加；3)研究IUGR胎盘中血管内皮生长因子表达急性上调的个体调控通路的功能。第一个具体目的是评估子宫动脉和静脉血流量和子宫摄氧量，以确定血流量减少或子宫过度缺氧是否是导致胎盘功能不全的初始损害。具体目标2和3将检查胎盘和分离的滋养细胞中表达的调节蛋白的表达和功能，以应对高温。这些实验方法所获得的信息将为PI-IUGR妊娠早期胎盘发育提供深入了解，并可能为未来恢复正常胎盘发育方法的发展提供基础信息。

DESCRIPTION (provided by applicant): Intrauterine growth restriction (IUGR) of the infant is a major cause of infant mortality and morbidity. Furthermore, research during the last decade provides compelling evidence that IUGR infants exhibit higher rates of coronary heart disease, type-2 diabetes, hypertension and stroke as adults. A majority of IUGR cases results from placenta insufficiency (PI), and it is our goal to develop an understanding of the underlying mechanisms of PI-IUGR, with the long-term aim of developing methods of intervention. Using a natural model of PI-IUGR in sheep, which shares many physiological and biochemical characteristics now documented in human IUGR pregnancies, we have observed both acute and chronic changes in placental gene expression as the IUGR pregnancy develops. Presently, it is our objective to determine the mechanisms of altered placental development that lead to PI-IUGR, focusing on the acute changes in placental development. 3 specific aims are planned: 1) To determine if uterine blood flow and oxygen uptake is acutely altered in the development of placental insufficiency; 2) To examine the cellular response within the IUGR placenta that leads to increased vascular endothelial growth factor expression; and 3) To examine the function of individual regulatory pathways responsible for acute up-regulation of vascular endothelial growth factor expression within the developing IUGR placenta. The first specific aim will assess uterine arterial and venous blood flow and uterine oxygen uptake to determine if reduced blood flow or excessive uterine hypoxia is the initial insults leading to placental insufficiency. Specific aims 2 and 3 will examine the expression and function of regulatory proteins expressed within placenta and isolated trophoblast cells, in response to hyperthermia. The information yielded by these experimental approaches will provide insight into early placental development of PI-IUGR pregnancies, and may provide the base information for the future development of methods to resurrect normal placental development.