Adrenomedullin Signaling at the Maternal-Fetal Interface

 描述（申请人提供）：肾上腺髓质素（AM）是一种多功能肽，参与多种生物学过程，包括胚胎发育、血管生成、心脏保护和先天免疫。在正常妊娠期间，母体血浆AM水平显著升高，但异常低水平通常与各种妊娠并发症相关，包括先兆子痫、胎儿生长受限、妊娠期糖尿病和自然流产。使用基因工程小鼠模型，我们的实验室是第一个证明母体AM的单倍不足导致与异常着床和胎儿生长受限相关的多种生殖缺陷。我们还发现，胎儿来源的AM是必要的适当重塑母亲的螺旋动脉-一个新的证明的重要性，胎儿与母亲的沟通在怀孕期间。总体而言，我们的研究表明，AM肽在母胎界面的剂量和信号传导是确保正常妊娠和分娩的重要方面。因此，我们打算在这些发现的基础上提出以下问题：“AM的剂量如何以及为什么在母胎界面得到精确调节？“使用复杂的遗传小鼠模型和体外药理学和细胞生物学测定，我们计划在三个独立的目标中解决这个广泛的问题。在具体目标1，我们将测试的假设，新的特点诱饵趋化因子受体，CXCR 7，作为一个“生物变阻器”AM介导的活动在早期植入和胎盘。具体目标2将测试胎儿滋养层细胞中AM基因表达的剂量通过由母体因素如妊娠激素和环境因素如香烟烟雾诱导的细胞内在miRNA的离散子集来平衡的假设。在具体目标3中，我们将进一步阐明AM对螺旋动脉（SA）重塑影响的独特细胞过程和分子机制。我们的研究结果将进一步加深我们对胎盘中控制母体-胎儿通讯的分子和过程的基本理解，并有可能为改善妊娠并发症提供新的临床诊断工具和治疗方法。

 DESCRIPTION (provided by applicant): 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. We also revealed that fetal-derived AM is required for the appropriate remodeling of maternal spiral arteries-a novel demonstration of the importance of fetal-to-maternal communication during pregnancy. Collectively our studies have shown that the dosage and signaling of AM peptide at the maternal-fetal interface is an essential aspect to ensuring a normal pregnancy and birth. Therefore, we intend to build on these findings by asking: "How and why does the dosage of AM get precisely regulated at the maternal-fetal interface?" Using sophisticated genetic mouse models and in vitro pharmacological and cell biological assays, we plan to address this broad question in three discrete Aims. In Specific Aim 1, we will test the hypothesis that the newly characterized decoy chemokine receptor, CXCR7, acts as a "biological rheostat" for AM-mediated activity during early implantation and placentation. Specific Aim 2 will test the hypothesis that the dosage of AM gene expression in fetal trophoblast cells is balanced by a discrete subset of cell-intrinsic miRNAs that are induced by maternal factors such as pregnancy hormones and environmental factors, like cigarette smoke. In Specific Aim 3 we will further elucidate the distinct cellular process and molecular mechanisms that govern the effects of AM on spiral artery (SA) remodeling. Results from our studies will 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 diagnostic tools and therapeutic approaches for the amelioration of complications of pregnancy.