Physiological Genomics of Pregnancy

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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.