Physiological Genomics of Pregnancy

描述（由申请方提供）：哺乳动物物种利用称为胎生的生殖策略，胚胎/胎儿发育发生在雌性生殖道内。它需要形成专门的母体和胚外结构，以促进胚胎发生。灵长类动物和啮齿类动物在母体和胎儿组织之间形成了一种密切的联系，称为血绒膜胎盘形成。这种密切的联系促进了营养物质和废物的交换，但代价是增加了母体免疫系统攻击的风险。母体-胎儿界面（包括子宫胎盘血管系统）的建立以及母体、胎盘和胎儿活动的协调中断是妊娠失败的潜在原因，包括母体和胎儿的健康问题。调节妊娠的建立和维持的机制还不清楚，我们也不了解与妊娠相关的疾病的分子病因。我们建议利用一种独特的遗传策略，“染色体替代”，发现关键基因的建立和维持怀孕。将使用形态学、生理学、生物化学和分子生物学方法研究亲代和染色体取代品系大鼠的妊娠表型。具体来说，我们将研究两个亲本大鼠品系：Dahl SS品系，表现出“正常”的强大的怀孕性能和布朗挪威品系，表现出高发生率的妊娠失败。将这些亲本品系妊娠表型与具有渗入Dahl SS遗传背景的单个Brown Norway染色体的大鼠品系的妊娠表型进行比较。拟议的分析应导致有效的战略，以确定基因牵连的疾病导致妊娠失败。

DESCRIPTION (provided by applicant): Mammalian species utilize a reproductive strategy referred to as viviparity, whereby embryonic/fetal development occurs within the female reproductive tract. It necessitates the formation of specialized maternal and extraembryonic structures that facilitate embryogenesis. Primates and rodents have developed a close connection between maternal and fetal tissues referred to as hemochorial placentation. This close connection facilitates the exchange of nutrients and wastes at the expense of an increased risk of attack by the maternal immune system. Disruptions in the establishment of the maternal-fetal interface, including the uteroplacental vasculature and coordination of maternal, placental, and fetal activities are potential causes of pregnancy failure, including health problems of the mother and fetus. Mechanisms regulating the establishment and maintenance of pregnancy are not well understood, nor do we understand the molecular etiology of diseases associated with pregnancy. We propose to utilize a unique genetic strategy, 'chromosome substitution', to discover genes pivotal to the establishment and maintenance of pregnancy. The pregnancy phenotype of parental and chromosome-substituted strains of rats will be investigated using morphological, physiological, biochemical, and molecular biology approaches. Specifically we will investigate two parental rat strains: the Dahl SS strain, which exhibits 'normal' robust pregnancy performance and the Brown Norway strain, which exhibits high incidences of pregnancy failure. These parental strain pregnancy phenotypes will be compared to the pregnancy phenotypes of strains of rats with individual Brown Norway chromosomes introgressed into the Dahl SS genetic background. The proposed analysis should lead to effective strategies for identifying genes implicated in diseases leading to pregnancy failure.