Grant: Operating Grant

Placental abnormalities are proposed to contribute to a spectrum of defects ranging from early embryonic loss to intrauterine growth retardation. In fact, approximately 30% of all pregnancies, as defined by detection of the pregnancy hormone HCG, are lost before the second trimester. This high rate of early pregnancy loss has also been documented in couples after assisted reproduction technology. Early pregnancy loss and intrauterine growth retardation can not be accounted for solely by environmental factors such as smoking and drinking, suggesting that genetic mutations in the fetus and/or mother are also significant contributors to early pregnancy loss. In animal models, a large number of genes are known to be required for normal formation of the fetus and/or its associated placentas. However, little is understood or known about the cellular processes that these genes regulate. In a screen for genes that are important for survival during the fetal period we identified a mutation in a chaperone protein called TMED2. Chaperones such as TMED2 are required for movement of proteins within the cell. TMED2 is implicated in transport of proteins from their site of synthesis to different locations in the cell where they are modified and become functional. TMED2 is conserved in human and is highly expressed in the placenta however, the function of this gene in the placenta is not known. In this grant we propose to use both in vitro and in vivo models to identify the cellular and molecular mechanisms of TMED2 function during the fetal period. We hope that our work will reveal novel mechanisms into formation of the embryo and placenta. A better knowledge of the events which regulate placental development will enable generation of technology for screening and maybe counseling patients of their risks.