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.
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