Functional immunogenetics of fetal and placental development: the regulation of placentation by NK cell receptors and their trophoblast ligands

We have shown that specific combinations of maternal and fetal immune genes predispose to reproductive failure. We will now identify the specific alleles that predispose to reproductive failure in humans. We will correlate, for the first time, maternal and fetal immune genotypes of large cohorts of normal and abnormal human pregnancies with blood flow dynamics at the experimentally inaccessible human maternal fetal-interface. Informed by these human genetic data we have designed experiments in mice to determine the downstream consequences of the interactions between maternal NK cell receptors (NKR) genes and fetal Major Histocompatibility Complex (MHC) genes on reproductive success. We will investigate in vivo exactly how these interactions control the mechanisms of vascular remodelling, placental development and fetal growth. A combination of cellular assays and transcriptome analysis will reveal the pathways activated in both maternal NK cells and fetal trophoblast cells upon int eractions with one another in both species. Bringing together human and mouse genetics, quantitative in vivo and in vitro assays and uterine artery Dopplers, this proposal is poised to generate data that will lead to new approaches for prevention and treatment of devastating conditions such as pre-eclampsia, recurrent miscarriage, fetal growth restriction and unexplained stillbirth.