Intermedin / AM2 in Human Pregnancy

Intermedin / AM2 在人类妊娠中的作用

• 批准号: 7767466
• 负责人: Madhu Lata S. Chauhan
• 金额: $ 7.4万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-10 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7767466
• 关键词: Age; Agonist; Amino Acids; Binding; Binding Sites; Biological Process; Blood Circulation; Calcitonin; Calcitonin Gene-Related Peptide; Calcitonin-Gene Related Peptide Receptor; Cells; Choriocarcinoma; Complex; Consensus; Data; Eating; Estrogens; Exhibits; Exons; Family; Female; Fetal Growth Retardation; Fetal Weight; G Protein-Coupled Receptor Genes; Gastric Emptying; Goals; Homeostasis; Human; Human Genome; Hypotension; Infant; Infusion procedures; Introns; Laboratories; Lead; Lobe; Mediating; Messenger RNA; Modeling; Morphology; Mus; Names; Ovary; Peptides; Phylogenetic Analysis; Pilot Projects; Pituitary Gland; Placenta; Placental Growth Factor; Plasma; Platelet Factor 4; Pre-Eclampsia; Pregnancy; Prolactin-Releasing Hormone; Proteins; RAMP2; RAMP3; Rattus; Reporting; Response Elements; Role; Serum; Site; Staging; Structure; Tissues; Umbilical Cord Blood; Umbilical cord structure; Uterus; Vascular Endothelial Growth Factors; Vertebrates; Villous; Weight; Woman; adrenomedullin; adrenomedullin receptor; base; calcitonin receptor-like receptor; cytotrophoblast; falls; implantation; islet amyloid polypeptide; member; novel; peptide hormone; pregnant; promoter; protein complex; protein expression; receptor; receptor binding; receptor-activity-modifying protein; reproductive function; trophoblast

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.

描述（由申请人提供）：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、激素，对体内平衡很重要。 CT/CGRP 肽家族的新成员 intermedin (IMD) 或 adrenomedullini (AN/k) 是两个研究小组于 2004 年同时独立发现的。 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含量高于 AM。 IMD 通过共同的受体复合物发挥作用，其生物学功能可能与 CGRP 和 AM 相似或重叠。事实上，与 AM 和 CGRP 一样，IMD 据报道可以降低正常和高血压大鼠的血压，具有心脏保护作用，抑制胃排空和食物摄入，并受雌激素调节。最近的报告表明，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发挥作用。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，并且 IMD mRNA 在植入部位和胎盘中表达，并在胎盘中受到妊娠调节。此外，怀孕大鼠第15至18天输注EVID拮抗剂（IMDi7.47）会导致胎盘和胎儿重量显着下降；胎盘生长因子（P1GF）和血管内皮生长因子蛋白（VEGF）并导致胎盘形态受损。我们实验室的进一步初步研究表明，IMD mRNA 在妊娠第 1 个月的 HTR-8/SV 新生滋养层细胞、绒毛膜癌 JAr 细胞和第 3 个月的人胎盘绒毛组织中表达。这些观察结果使我们推测 IMD 在人类妊娠中发挥作用，特别是血浆 IMD、胎盘 EVID 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：确定女性循环中的免疫反应性 IMD 水平是否会随着怀孕而增加，而在产后会减少。具体目标 2：评估 IMD mRNA 和 IMD 受体 mRNA 和蛋白质水平，表征 IMD 受体结合位点，并证明它们在不同妊娠阶段的人胎盘中的细胞定位。具体目标3：确定先兆子痫、IUGR和先兆子痫伴IUGR的女性与年龄匹配的正常女性相比，血浆IMD水平以及胎盘中IMD及其受体成分的表达是否降低；评估正常、IUGR、先兆子痫和先兆子痫伴 IUGR 妊娠的脐带血中 EVID 的血浆浓度，并与婴儿体重相关。