Genetics of Decidualization

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DESCRIPTION (provided by applicant): Successful embryonic development within the female reproductive tract requires the generation of a specialized maternal structure, the decidua. Decidual cells are modified uterine endometrial stromal cells. During gestation, decidual cells are located at the interface separating invading trophoblast cells from the maternal environment. They protect and facilitate the flow of nutrients to the embryo. These decidual cell tasks are accomplished via modulation of maternal uterine vascular development, immunology, and metabolism. Pregnancy is dependent upon decidual cell acquisition of these specialized functions. Mechanisms regulating the establishment of pregnancy are not well understood, nor do we understand the molecular etiology of diseases associated with early pregnancy loss. Disruptions in the coordination of uterine adaptations to pregnancy are potential causes of gestational failure. We propose to utilize a unique genetic strategy, 'chromosome substitution', to discover genes pivotal to the establishment of pregnancy and more specifically to the process of decidualization. Our analyses are based on genetic differences in pregnancy performance in Dahl SS (DSS) and Fawn HH (FHH) strains, which exhibit 'normal' robust pregnancy performance versus the Brown Norway (BN) strain, which exhibits a high incidence of pregnancy failure. In the first specific aim, decidualization phenotypes of chromosome-substituted (consomic) strains of rats will be assessed. Decidualization phenotypes will be determined in consomic strains possessing individual BN chromosomes introgressed into either the DSS or the FHH genetic backgrounds. In the second specific aim, the analysis will focus on Chromosome 18, which has been implicated as the location of genes impacting decidualization. Our planned experimentation includes morphological, physiological, biochemical, and molecular biology approaches. The proposed research should lead to effective strategies for identifying genes critical for the establishment of pregnancy and genes implicated in diseases leading to early pregnancy failure. PUBLIC HEALTH RELEVANCE: Early pregnancy failure is a significant health problem. The appropriate development and functioning of decidual cells is essential for the establishment and maintenance of pregnancy. Elucidation of the genetics of decidual cell development is a key to understanding the etiology of early pregnancy failure.