Intermedin / AM2 in Human Pregnancy

性状（由申请方提供）：降钙素（CT）、降钙素基因相关肽CGRP、胰淀素和肾上腺髓质素（AM）属于一组独特的肽类激素，对体内平衡很重要。CT/CGRP肽家族的新成员--中间肽（intermedin，IMD）或肾上腺髓质素（adrenomedullini，AN/k）是2004年由两个研究小组同时独立发现的。IMD通过CGRP和AM受体复合物发挥作用，并具有与AM相似的内含子-外显子结构。IMD在大鼠和小鼠血液循环中的水平高于AM。通过共同的受体复合物发挥作用，IMD可能具有与CGRP和AM相似或重叠的生物学功能。事实上，与AM和CGRP一样，IMD被报道在正常和高血压大鼠中降低血压，表现出心脏保护作用并抑制胃排空和食物摄入，并且受雌激素调节。最近的报道表明，IMD mRNA在包括子宫和卵巢在内的多种组织中表达，表明该肽在女性生殖功能中可能起作用。我们使用大鼠模型进行的初步研究表明，大鼠血浆中IMD的循环水平受到妊娠调节，IMD mRNA在着床部位和胎盘中表达，并在胎盘中受到妊娠调节。此外，在妊娠大鼠中从第15天至第18天输注IMD拮抗剂（IMDi7.47）导致胎盘和胎仔重量、胎盘生长因子（P1 GF）和血管内皮生长因子蛋白（VEGF）显著下降，并导致胎盘形态受损。本实验室的进一步初步研究表明，IMD mRNA在妊娠早期HTR-8/SV neo滋养层细胞、绒毛膜癌JAr细胞和妊娠晚期人胎盘绒毛组织中表达。这些观察结果使我们假设IMD在人类妊娠中具有作用，特别是血浆IMD、胎盘IMD及其受体的水平随着妊娠的进展而增加，并且这些增加在患有先兆子痫和/或IUGR的女性中受到损害。本研究的具体目的是：具体目的1：确定女性的免疫反应性IMD水平的循环水平是否随妊娠而增加，并在产后降低。具体目标二：评估IMD mRNA和IMD受体mRNA和蛋白水平，表征IMD受体结合位点，并证明其在妊娠不同阶段人胎盘中的细胞定位。具体目标3：确定与年龄匹配的正常妇女相比，患有先兆子痫、IUGR和先兆子痫伴IUGR的妇女的血浆IMD水平和胎盘中IMD及其受体组分的表达是否降低;并评估来自正常、IUGR、先兆子痫和先兆子痫伴IUGR妊娠的脐带血中IMD的血浆浓度并与婴儿体重相关。

DESCRIPTION (provided by applicant): Calcitonin (CT), calcitonin gene related peptide CGRP, amylin and adrenomedullin (AM) belong to a unique group of peptide, hormones, important for homeostasis. A new member of CT/CGRP peptide family, intermedin (IMD) or adrenomedullini (AN/k), was discovered in 2004 independently and simultaneously by two groups. IMD functions through both, CGRP and AM receptor complexes and possesses intron-exon structures similar to AM. IMD is present in rat and mice blood circulation at a level higher than AM. Functioning through common receptor complexes, IMD may have biological functions similar to, or overlapping with CGRP and AM. Indeed, like to AM and CGRP, IMD in reported to lower blood pressure in normal and hypertensive rats, exhibits cardioprotective effects and suppress gastric emptying and food intake and is regulated by estrogen. Recent reports show that IMD mRNA is expressed by various tissues including uterus and ovary indicating a possible role of this peptide in female reproductive functions. Our preliminary studies using rat models indicate that circulatory levels of IMD in rat plasma are gestationally regulated, and IMD mRNA is expressed in implantation sites and placenta and is gestationally regulated in placenta. In addition, infusion of EVID antagonist (IMDi7.47) from Day 15 to 18 in pregnant rats caused a significant decline in placental and fetal weights; placental growth factors (P1GF) and vascular endothelial growth factor protein (VEGF) and caused impaired placental morphology. Further pilot studies in our laboratory show that IMD mRNA is expressed in 1st trimester HTR-8/SV neo trophoblast cells, choriocarcinoma JAr cells and 3rd trimester human placental villous tissue. These observations lead us to hypothesize that IMD has a role in human pregnancy, in particular The levels of plasma IMD, placental EVID and its receptors are increased with advancement of gestation and these increases are compromised in women with preeclamptic and/or IUGR. Specific aims of this study are: Specific Aim 1: To determine if circulatory levels of immunoreactive IMD levels in women are increased with pregnancy and decreased post-partum. Specific Aim 2: To assess IMD mRNA and IMD receptor mRNA and protein levels, characterize IMD receptor binding sites, and demonstrate their cellular localization in human placenta on different stages of gestation. Specific Aim 3: To determine if plasma IMD levels and the expression of IMD and its receptor components in placenta are decreased in women with preeclampsia, IUGR, and preeclampsia with IUGR compared to that of age-matched normal women; and to assess plasma concentration of EVID in umbilical cord blood from normal, IUGR, preeclampsia and preeclampsia with IUGR pregnancies and correlate with the infant weights.