The overall objective of this proposal is to define the essential molecular mechanisms that underlie uterine receptivity. Ovarian-derived progesterone is known to be an indispensable signaling molecule in the preparation of the uterus for embryo attachment and subsequent invasion Using the progesterone receptor knockout mouse in combination with DNA microarray technology, we recently demonstrated that the morphogen, Indian hedgehog, Ihh, is expressed in the murine uterus and, importantly, regulated by progesterone via its nuclear receptor. This important observation forms the basis of the following hypothesis: The Indian hedgehog signaling pathway is an integral regulatory axis for the preparation of the uterus for embryonic implantation. This proposal will establish a novel mouse model for the reproductive tissue specific ablation of Ihh and then evaluate the impact of Ihh ablation on uterine function. Then, this proposal will investigate the expression of members of the Ihh signaling cascade in human endometrial tissue. Then, this proposal will investigate the expression of members of the Ihh signaling cascade in human endometrial tissue. The goals of this proposal will be achieved by using Homologous recombination in ES cells to insert Cre recombinase into the progesterone receptor locus. This mouse will be used to ablate Ihh specifically in the uterus and mouse reproductive tissues. The physiologic and molecular impact of Ihh ablation in the uterus will then be investigated. Finally the expression of Ihh in the receptive and non-receptive human endometrium will be investigated. The contribution of this proposal to the U01 consortium will be the establishment of a novel animal model that will facilitate the investigation of the role of regulatory molecule sin uterine receptivity, as well as, the investigation of the role and expression of members of the Ihh signaling cascade in mouse and human receptivity.

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 #
5U01HD042311-02
Application #
6626019
Study Section
Special Emphasis Panel (ZHD1-RRG-K (12))
Program Officer
Tasca, Richard J
Project Start
2002-04-01
Project End
2007-03-31
Budget Start
2003-04-01
Budget End
2004-03-31
Support Year
2
Fiscal Year
2003
Total Cost
$290,218
Indirect Cost
Name
Baylor College of Medicine
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
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Monsivais, Diana; Clementi, Caterina; Peng, Jia et al. (2016) Uterine ALK3 is essential during the window of implantation. Proc Natl Acad Sci U S A 113:E387-95
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Jeong, Jae-Wook; Lee, Hee Sun; Lee, Kevin Y et al. (2009) Mig-6 modulates uterine steroid hormone responsiveness and exhibits altered expression in endometrial disease. Proc Natl Acad Sci U S A 106:8677-82
Fernandez-Valdivia, Rodrigo; Mukherjee, Atish; Ying, Yan et al. (2009) The RANKL signaling axis is sufficient to elicit ductal side-branching and alveologenesis in the mammary gland of the virgin mouse. Dev Biol 328:127-39

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