Adrenomedullin Signaling at the Maternal-Fetal Interface

项目摘要

Project Abstract Adrenomedullin (AM) is a multifunctional peptide that is involved in a variety of biological processes, including embryonic development, angiogenesis, cardio-protection, and innate immunity. Maternal plasma levels of AM rise substantially during a normal pregnancy, but abnormally low levels are often associated with a variety of pregnancy complications including preeclampsia, fetal growth restriction, gestational diabetes and spontaneous abortion. Using genetically engineered mouse models, our laboratory was the first to demonstrate that haploinsufficiency for maternal AM causes a multitude of reproductive defects associated with abnormal implantation and fetal growth restriction. More recently, we extended these findings to humans by identifying the first loss-of-function mutation in the AM G protein-coupled receptor CALCRL, associated with hydrops fetalis, placental edema and maternal subfertility. Collectively our prior studies have defined the ways in which dosage of AM peptide and receptors can impact reproductive success, in animal models and in humans. Therefore, in this competitive renewal we are uniquely positioned to extend on our previous work by asking the overarching “bench-to- bedside” question of " How does AM signaling affect its target cells during implantation and placentation and whether extrinsic factors can alter levels of AM to exert physiological effects on pregnancy outcomes?" The focus of our studies places AM signaling as a cornerstone for elucidating fundamental questions related to pinopode formation (Aim 1), growth and remodeling of placental/decidual vasculature (Aim 2) and the roles of extrinsic environmental factors on reproductive outcomes (Aim 3). Using sophisticated genetic mouse models and in vitro pharmacological and cell biological assays, we intend to further our basic understanding of molecules and processes that govern maternal-to-fetal communication in the placenta and have the potential of providing new clinical therapeutic targets for the amelioration of complications of pregnancy.