The long-term objective of this research proposal is to explore the molecular basis of the regulation of embryonic implantation by calcitonin (CT), a peptide hormone that regulates calcium homeostasis. The expression of CT is induced in the glandular epithelium of rat uterus in the preimplantation phase of gestation and is switched off once implantation is completed. CT expression in human endometrium is restricted to the mid- secretory phase (days 19-24) of the menstrual cycle, with closely overlaps with the putative window of implantation. These findings suggest that CT may function as an important regulatory signal in the uterus during implantation.
The specific aims of this proposal are: 1. To determine the functional event(s) regulated by CT during implantation. Administration of antisense oligodeoxynucleotides (ODNs), targeted against CT mRNA, into the preimplantation phase uterus results in marked suppression of the steady-state level of uterine CT mRNA. This intervention is also accompanied by a severe reduction in the number of implanted embryos. These results suggest that the impairment of implantation could be a direct phenotypic consequence of the blockade of CT gene expression by the antisense ODN. The effect of antisense ODN-induced CT deficiency on (a) uterine receptivity and (b) the ability of the embryo to implant will be examined by embryo transfer experiments. 2. To elucidate the signal transduction pathway(s) of CT in transformed human endometrial cell line Ishikawa and in primary cultures of human endometrial epithelial cells. CT acts on target cells through specific cell surface receptors. The expression of the CT receptor is also markedly elevated in the preimplantation endometrial epithelium. The second messenger pathways that are activated by CT via its receptor will be investigated in Ishikawa and primary cultures of endometrial epithelial cells. 3. To identify the genes that mediate the cellular actions of CT. CT stimulates the expression of c-fos mRNA while it inhibits the expression of osteopontin mRNA in human endometrial cells. To further understand how CT influences the embryo-uterine interactions, additional genes whose expression in the target cells is modulated in response to this hormone will be identified by subtractive cloning and their spatio-temporal expression in human endometrium during the menstrual cycle will be determine. The proposed study will provide valuable insights into the molecular mechanisms underlying the chain of events that link the transient expression of CT in the uterine glands to the control of embryo-endometrial interactions during implantation.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD034527-07
Application #
6521006
Study Section
Reproductive Endocrinology Study Section (REN)
Program Officer
Yoshinaga, Koji
Project Start
1996-09-30
Project End
2004-06-30
Budget Start
2002-07-01
Budget End
2004-06-30
Support Year
7
Fiscal Year
2002
Total Cost
$272,577
Indirect Cost
Name
University of Illinois Urbana-Champaign
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
041544081
City
Champaign
State
IL
Country
United States
Zip Code
61820
Li, Quanxi; Bagchi, Milan K; Bagchi, Indrani C (2006) Identification of a signaling pathway involving progesterone receptor, calcitonin, and tissue tranglutaminase in Ishikawa endometrial cells. Endocrinology 147:2147-54
Cheon, Yong-Pil; DeMayo, Francesco J; Bagchi, Milan K et al. (2004) Induction of cytotoxic T-lymphocyte antigen-2beta, a cysteine protease inhibitor in decidua: a potential regulator of embryo implantation. J Biol Chem 279:10357-63
Kumar, Sushma; Brudney, Allison; Cheon, Yong-Pil et al. (2003) Progesterone induces calcitonin expression in the baboon endometrium within the window of uterine receptivity. Biol Reprod 68:1318-23
Bagchi, Indrani C; Cheon, Yong-Pil; Li, Quanxi et al. (2003) Progesterone receptor-regulated gene networks in implantation. Front Biosci 8:s852-61
Cheon, Yong-Pil; Xu, Xueping; Bagchi, Milan K et al. (2003) Immune-responsive gene 1 is a novel target of progesterone receptor and plays a critical role during implantation in the mouse. Endocrinology 144:5623-30
Li, Quanxi; Wang, Jun; Armant, D Randall et al. (2002) Calcitonin down-regulates E-cadherin expression in rodent uterine epithelium during implantation. J Biol Chem 277:46447-55
Cheon, Yong-Pil; Li, Quanxi; Xu, Xueping et al. (2002) A genomic approach to identify novel progesterone receptor regulated pathways in the uterus during implantation. Mol Endocrinol 16:2853-71
Kumar, S; Angervo, M; Bagchi, M K et al. (2001) Isolation of steroid-regulated genes from the uterus by mRNA differential display. Methods Mol Biol 176:105-17
Kumar, S; Li, Q; Dua, A et al. (2001) Messenger ribonucleic acid encoding interferon-inducible guanylate binding protein 1 is induced in human endometrium within the putative window of implantation. J Clin Endocrinol Metab 86:2420-7
Li, Q; Zhang, M; Kumar, S et al. (2001) Identification and implantation stage-specific expression of an interferon-alpha-regulated gene in human and rat endometrium. Endocrinology 142:2390-400

Showing the most recent 10 out of 17 publications