Adrenomedullin Signaling at the Maternal-Fetal Interface

项目摘要 肾上腺髓质素(adrenomedullin，AM)是一种多功能多肽，参与多种生物效应。 过程，包括胚胎发育、血管生成、心脏保护和先天 豁免权。正常妊娠期间，母体血浆AM水平显著升高，但 异常的低水平通常与各种妊娠并发症有关，包括 子痫前期、胎儿生长受限、妊娠期糖尿病和自然流产。vbl.使用 转基因小鼠模型，我们的实验室是第一个证明 母体AM的单倍体不足会导致大量生殖缺陷，与 植入异常和胎儿生长受限。最近，我们将这些发现扩展到 通过鉴定AM G蛋白偶联受体中的第一个功能丧失突变来识别人类 CALCRL与胎儿积水、胎盘浮肿和母体不孕有关。集体地 我们先前的研究已经确定了AM多肽和受体的剂量可以影响 动物模型和人类的生殖成功。因此，在这场竞争性更新中，我们 都处于独特的地位，可以通过要求最重要的“板凳到- 床边的“问题”：AM信号如何影响着床过程中的靶细胞 胎盘形成和外在因素是否能改变AM水平对胎盘产生生理影响 妊娠结局？“我们研究的重点是将AM信号作为 阐明与针柄形成(目标1)、生长和重塑有关的基本问题 胎盘/蜕膜血管系统(目标2)和外部环境因素在胎盘/蜕膜血管形成中的作用 生殖成果(目标3)。使用复杂的小鼠遗传模型和体外 药理学和细胞生物学检测，我们打算加深我们对 控制胎盘中母婴沟通的分子和过程，并具有 为改善脑出血并发症提供新的临床治疗靶点的潜力 怀孕了。

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.