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.
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