Description): The long-term objective of this research proposal is to identify molecular markers that are unique and sensitive indicators of the receptive state of human endometrium during embryo implantation. The endometrium can accept a developing blastocyst for implantation only during a limited period of time, termed the receptive phase, during the menstrual cycle. The molecular events underlying uterine receptivity remain unknown.
The Specific Aims of this proposal are: (1) To examine the temporal and spatial expression of calcitonin in human endometrium during the menstrual cycle. Preliminary studies show that the expression of calcitonin, a peptide hormone that regulates calcium homeostasis, is induced in the glandular epithelium of human endometrium around the mid-secretory phase of the menstrual cycle but is undetectable in the proliferative phase. Since it is thought that the window of implantation in the human opens between days 19-23 of the cycle, these results suggest that calcitonin may function as a potential marker of implantation. To evaluate this possibility, the profile of calcitonin expression in human endometrium during the menstrual cycle will be examined in detail by in situ hybridization and immunohistochemistry. (2) To identify additional potential markers of uterine receptivity for embryo implantation in the human. Messenger RNA differential display (DD) technique will be used to isolate cDNAs corresponding to additional potential marker genes that are expressed in human endometrium specifically during the mid-secretory phase of the menstrual cycle, the putative time of implantation. The spatio-temporal expression of these candidate marker genes will be examined in the endometrium during the menstrual cycle. (3) To assess the functional roles of potential markers of uterine receptivity during implantation. A method employing antisense oligodeoxynucleotide (ODN) was developed in this laboratory to manipulate the expression of specific genes in rat uterus. Administration of antisense ODN, directed against a specific mRNA, into the preimplantation phase uterus was shown to suppress the steady-state level of the targeted mRNA around the time of implantation. Blockade of expression of a gene that controls uterine receptivity would impair implantation. The antisense ODN approach in the rat model system will therefore be used to evaluate the functional consequence of the attenuation of expression of candidate marker genes that will be isolated from human endometrium by the DD technique.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01HD034760-03
Application #
2838832
Study Section
Special Emphasis Panel (SRC (18))
Program Officer
Tasca, Richard J
Project Start
1996-12-01
Project End
2000-11-30
Budget Start
1998-12-01
Budget End
1999-11-30
Support Year
3
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Population Council
Department
Type
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10017
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
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
Bagchi, I C; Li, Q; Cheon, Y P (2001) Role of steroid hormone-regulated genes in implantation. Ann N Y Acad Sci 943:68-76
Carson, D D; Bagchi, I; Dey, S K et al. (2000) Embryo implantation. Dev Biol 223:217-37
Chen, D; Ganapathy, P; Zhu, L J et al. (1999) Potential regulation of membrane trafficking by estrogen receptor alpha via induction of rab11 in uterine glands during implantation. Mol Endocrinol 13:993-1004
Chen, D; Xu, X; Zhu, L J et al. (1999) Cloning and uterus/oviduct-specific expression of a novel estrogen-regulated gene (ERG1) J Biol Chem 274:32215-24
Bagchi, I C; Kumar, S (1999) Steroid-regulated molecular markers of implantation. Semin Reprod Endocrinol 17:235-40
Zhu, L J; Cullinan-Bove, K; Polihronis, M et al. (1998) Calcitonin is a progesterone-regulated marker that forecasts the receptive state of endometrium during implantation. Endocrinology 139:3923-34

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