Molecular Analysis of Uterine Receptivity

描述(由申请人提供)：本提案的总体目标是确定支持胚胎植入的子宫准备的基本分子机制。具体地说，这项建议将研究卵巢类固醇激素黄体酮(P4)在植入前子宫中调节的分子通路。P4通过其同源核受体，孕激素受体(PR)，调节基因的转录，这些基因协调子宫支持胚胎植入和胎儿发育的能力。P4信号的改变与子宫内膜疾病有关，如不孕症、子宫内膜异位症和子宫内膜癌。在上一次资助期间，我们已经证明，在小鼠子宫中有条件地消融IHH会导致间质细胞的增殖、血管形成和分化的丧失。这种表型导致子宫不能发生植入后的蜕膜反应。除了对子宫内膜间质功能的调节外，IHH信号失活还干扰了子宫内膜上皮支持胚胎附着和侵袭的能力。我们有初步的数据表明，消融IHH导致子宫内膜上皮中雌激素受体α(ER1)和雌激素(E2)调节基因的表达增加。这项应用的第一个目标是检验这样一种假设，即子宫上皮对E2的敏感性增加是由于IHH表达缺失导致植入缺陷的原因。然后，我们将通过确定IHH在白血病抑制因子(LIF)信号轴中的调节和作用来进一步研究P4调节的IHH通路与E2信号的相互作用。LIF信号轴是一条E2调节的通路，对正常着床至关重要。最后，鉴于PR-IHH轴在调节子宫功能中的重要性，我们将确定PR调节IHH表达的分子机制。这将通过三个具体目标来实现。(1)探讨IHH消融后子宫内膜上皮细胞E2信号增强对子宫容受性的生理意义。(2)IHH信号轴与E_2调节的白血病抑制因子(LIF)信号轴在胚胎着床子宫准备过程中的相互作用。(3)子宫内膜上皮PR调节IHH表达和子宫功能的分子机制将在体内明确。这项提案的目标的完成将确定P4调节通路在调节子宫上皮功能中的作用。公共卫生相关性：不孕症、子宫内膜异位症和子宫内膜癌对妇女的健康有很大影响。这个项目将确定类固醇和黄体酮在这些疾病中的作用。

DESCRIPTION (provided by applicant): The overall objective of this proposal is to define the essential molecular mechanisms that underlie the preparation of the uterus to support embryo implantation. Specifically, this proposal will investigate the molecular pathways regulated by the ovarian steroid hormone, progesterone (P4), in the pre-implantation uterus. P4 acting through its cognate nuclear receptor, the progesterone receptor (PR), regulates the transcription of genes which coordinate the ability of the uterus to support embryo implantation and fetal development. Alterations in P4 signaling are associated with endometrial diseases, such as infertility, endometriosis and endometrial cancer. During the last funding period, we have demonstrated that conditional ablation of Ihh in the murine uterus results in loss of stroma cell proliferation, vascularization, and differentiation. This phenotype resulted in the inability of the uterus to undergo the post-implantation decidual reaction. In addition to the regulation of endometrial stroma function, inactivation of Ihh signaling interfered with the ability of the endometrial epithelium to support embryo attachment and invasion. We have preliminary data illustrating that ablation of Ihh results in an increase in the expression of Estrogen Receptor alpha (ER1) and estrogen (E2) regulated genes in the endometrial epithelium. The first goal of this application is to test the hypothesis that the increased E2 sensitivity in the uterine epithelium is the cause of the implantation defect due to loss of Ihh expression. We will then further investigate the interaction of the P4 regulated Ihh pathway with E2 signaling by determining the regulation by and role of Ihh in the Leukemia Inhibitory Factor (Lif) signaling axis, an E2 regulated pathway that is critical for normal implantation. Finally, given the importance of the PR-Ihh axis in the regulation of uterine function, we will define the molecular mechanism by which PR regulates the expression of Ihh. This will be accomplished in three specific aims. (1) The physiological significance of the increased E2 signaling in the endometrial epithelium after ablation of Ihh on uterine receptivity will be investigated. (2) The interaction of the Ihh signaling axis with that of the E2 regulated Leukemia Inhibitory Factor (Lif) signaling axis in the preparation the uterus for embryo implantation will be identified. (3) The molecular mechanism by which endometrial epithelial PR regulates the expression of Ihh and uterine function will be defined in vivo. The completion of the aims of this proposal will define the role of P4 regulated pathways in the regulation of uterine epithelial function. PUBLIC HEALTH RELEVANCE: Infertility, endometriosis, and endometrial cancer have a large affect on women's health. This project will determine the role the steroid, progesterone has on these diseases.