Intermedin / AM2 in Human Pregnancy

点击翻译按钮获取中文摘要

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.