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. ? ? ? ?

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Small Research Grants (R03)
Project #
5R03HD054867-02
Application #
7393839
Study Section
Pediatrics Subcommittee (CHHD)
Program Officer
Ilekis, John V
Project Start
2007-04-10
Project End
2010-03-31
Budget Start
2008-04-01
Budget End
2010-03-31
Support Year
2
Fiscal Year
2008
Total Cost
$73,990
Indirect Cost
Name
University of Texas Medical Br Galveston
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
800771149
City
Galveston
State
TX
Country
United States
Zip Code
77555
Chauhan, Madhu; Balakrishnan, Meena; Vidaeff, Alex et al. (2016) Adrenomedullin2 (ADM2)/Intermedin (IMD): A Potential Role in the Pathophysiology of Preeclampsia. J Clin Endocrinol Metab 101:4478-4488
Chauhan, Madhu; Balakrishnan, Meena; Chan, Rexanna et al. (2015) Adrenomedullin 2 (ADM2) Regulates Mucin 1 at the Maternal-Fetal Interface in Human Pregnancy. Biol Reprod 93:136
Havemann, Dara; Balakrishnan, Meena; Borahay, Mostafa et al. (2013) Intermedin/adrenomedullin 2 is associated with implantation and placentation via trophoblast invasion in human pregnancy. J Clin Endocrinol Metab 98:695-703
Yallampalli, Chandra; Chauhan, Madhu; Sathishkumar, K (2013) Calcitonin gene-related family peptides in vascular adaptations, uteroplacental circulation, and fetal growth. Curr Vasc Pharmacol 11:641-54
Chauhan, Madhu; Balakrishnan, Meena; Yallampalli, Uma et al. (2011) Adrenomedullin 2/intermedin regulates HLA-G in human trophoblasts. Biol Reprod 85:1232-9
Chauhan, Madhu; Elkins, Rebekah; Balakrishnan, Meena et al. (2011) Potential role of intermedin/adrenomedullin 2 in early embryonic development in rats. Regul Pept 170:65-71
Chauhan, Madhu; Yallampalli, Uma; Dong, Yuan-Lin et al. (2009) Expression of adrenomedullin 2 (ADM2)/intermedin (IMD) in human placenta: role in trophoblast invasion and migration. Biol Reprod 81:777-83