Regulation of maspin in placental development

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DESCRIPTION (provided by applicant): Placental invasion is a highly regulated process and impairment results in pathologic obstetric conditions such as preeclampsia and intra-uterine growth restriction (IUGR). Further identification of factors that play a role in modifying this invasive ability of cytotrophoblasts will contribute to a better understanding of this unique developmental process. We have demonstrated a specific timeline for the expression of maspin, novel tumor suppressor gene in placental invasion and development. Our findings show that maspin is maximally expressed in the third trimester with low levels of expression in the first trimester of pregnancy. The specific aims of this proposal are 1) To measure the biological consequence(s) of maspin up regulation in human cytotrophoblasts with respect to invasion, motility and morphogenesis in vitro 2) Examine the role of hypoxia in regulating maspin expression in cytotrophoblasts 3) Compare the abundance of maspin/manganese superoxide dismutase mRNA and protein in placentas from women with term and preterm deliveries, with and without preeclampsia. The research design will include using adenoviral approach to transfect maspin into primary trophoblast cultures during the first and second testers and examine the effects of this transfection on cell invasion, migration, motility and morphogenesis. Next, the effects of hypoxia on maspin expression and the role of hypoxia-inducible factor in mediating these effects will be examined. Finally, will confirm our hypothesis using an in vivo model of hypoxia and impaired cytotrophoblast invasion namely preeclampsia. Maspin expression will be compared in placentae from women with preeclampsia to those from normal controls using real-time PCR. The long-term objectives of this project are two-fold, first, to understand the significance and mechanism(s) of action of tumor suppressor genes such as maspin in human placental development second, to identify pathological processes during gestation arising from alterations of maspin expression. Information revealed in this study could have profound implications on therapeutic strategies for clinical conditions associated with decreased cytotrophoblast invasion such as preeclampsia and IUGR. In addition, any important new information that may be obtained about the putative role of maspin during embryonic development may help elucidate the biological significance of its loss during tumor progression.