The physiological and genetic mechanisms responsible for normal placentation and how their perturbation impairs placental blood flow to cause fetal growth restriction (FGR) remain largely unknown. Adrenomedullin (Adm) is a peptide vasodilator that has significant roles during pregnancy. A genetically deficient Adm mouse line is presented as a genetically-induced model of FGR and phenotyping of this model will elucidate the role of Adm in pregnancy and fetal growth. The Iong term objectives of this grant, to reveal the role of Adm in reproduction and to identify genetic and physiological factors that contribute to mechanisms of FGR will be achieved in three aims.
Specific Aim I will test the hypothesis that local concentrations of Adm at the maternal-fetal interface are essential for normal placentation and fetal .qrowth. To distinguish between the maternal and fetal contribution of Adm, a novel approach of .qenetically predetermined blastocyst transfer will be used. Pregnancies will be monitored for physiological and pathological indications of preeclampsia and placentas will be analyzed by 3-Dimensional placental casts, histology, ultrasound Doppler and the molecular phenotyping approach described in Specific Aim 2.
Specific Aim 2 will develop and validate a novel method for characterizinq placental defects by quantitaion of surrogate gene expression markers to determine if there are common placental pathways that are disrupted in association with FGR. Validation and application of this high-throughput phenotyping screen will be done in collaboration with the N/H-funded Mouse Mutagenesis Center for Deve/opmental Defects at Bay or Col/ege of Medicine.
Specific Aim 3 will combine the novel methods of Aims 1 & 2 to ask how maternal chronic diseases, such as hypertension and preeclampsia, exacerbate FGR. Four hypertensive mouse lines, including a genetically-clamped renin transgenic line, a genetically-deficient NPRA line, a genetically-deficient eNOS line and a spontaneously preeclamptic BPH/5 line will be used. Quantitative and comparative evaluation of the phenotypes will identify common genetic mechanisms that underlie the association between maternal hypertension and FGR. Each of the Specific Aims addresses gaps in our current knowledge of the role of Adm in reproduction and the mechanisms underlying FGR. Thus, results from these studies will advance basic science, contribute to better human reproductive health and potentially identify therapeutic interventions that would favorably alter the course of fetal growth in humans.
