Modulation of the Receptive Endometrium by CG

描述（由申请人提供）：怀孕的开始需要子宫内膜发育和植入囊胚之间的精确时间同步。这个“接受窗口期”最初依赖于雌激素和黄体酮。然而，来自发育中的胚胎的信号进一步修饰了受体子宫。在之前的资助期间，我们在非人类灵长类动物模型中解决了这个问题。我们证明，除了雌激素和黄体酮在接受窗口期间引起的特定变化外，以模仿囊胚转运的方式输注绒毛膜促性腺激素（CG）进一步调节子宫环境。所有三种主要细胞类型，即腔上皮、腺上皮和间质成纤维细胞的变化都很明显。间质成纤维细胞骨架结构的调节和腺上皮细胞分泌活性的增加是由CG直接作用于子宫内膜而不依赖于卵巢来调节的。此外，当黄体酮受体被拮抗时，这些反应被抑制。由于我们的体内研究已经清楚地证明了CG对调节子宫容受性的直接作用，我们现在提出了一系列的研究来确定两种基因产物的功能，这两种基因产物是在CG刺激下在间质成纤维细胞中诱导的。基质细胞蛋白（Stromal Cell Protein， SCP）和Notch-1均在基质细胞中表达，在体内和体外均受CG调控。第一个特异性目标是确定SCP激活免疫细胞中的重组激活基因的机制，这反过来可能负责改变子宫内膜内淋巴细胞群的表型。我们假设这些调节机制在提供对胎儿同种异体移植物的免疫耐受方面发挥了核心作用。在第二个特定目标中，我们提出确定Notch-1在间质成纤维细胞中抑制细胞凋亡的作用。此外，Notch-1也能够影响淋巴系内表型分化的承诺。因此，这些研究将深入了解间质成纤维细胞在妊娠建立过程中发挥重要作用的机制。了解怀孕早期子宫环境中复杂的免疫和细胞分化机制与我们识别不孕、妊娠失败和其他可能导致女性不孕的原因直接相关。

DESCRIPTION (provided by applicant): The initiation of pregnancy requires a precisely timed synchrony between endometrial development and the implanting blastocyst. This "receptive window" is initially dependent on estrogen and progesterone. However, signals from the developing embryo further modify the receptive uterus. During the previous funding period we addressed this issue in a non-human primate model. We demonstrated that in addition to the specific changes that are induced by estrogen and progesterone during the window of receptivity, infusion of chorionic gonadotrophin (CG) in a manner that mimics blastocyst transit further modulates the uterine environment. Changes are evident in all three major cell types i.e., the luminal epithelium, glandular epithelium and stromal fibroblasts. The modulation of the cytoskeletal architecture in stromal fibroblasts and the increase in secretory activity in glandular epithelial cells are regulated by CG acting directly on the endometrium, independent of the ovary. Furthermore these responses are suppressed when the progesterone receptor is antagonized. Since our in vivo studies have clearly demonstrated a direct effect of CG on modulating uterine receptivity, we now propose a series of studies to determine the function of two gene products that are induced in stromal fibroblasts in response to CG stimulation. Stromal Cell Protein (SCP) and Notch-1 are both expressed in stromal cells and their expression is regulated both in vivo and vitro by CG. The first Specific Aim is focused on determining the mechanisms by which SCP activates Recombination Activating Gene in immune cells, which in turn may be responsible for altering the phenotype of lymphocyte populations within the endometrium. We hypothesize that these regulating mechanisms play a central role in providing immune tolerance to the fetal allograft. In the second Specific Aim we propose to determine the role of Notch-1 to inhibit apoptosis in stromal fibroblasts. In addition, Notch-1 is also able to influence the commitment to phenotypic differentiation within the lymphoid lineage. Thus, these studies will provide insight into the mechanisms by which stromal fibroblasts play an important role during the establishment of pregnancy. Understanding the complex immune and cell differentiation mechanisms within the uterine environment during early pregnancy has direct relevance to our ability to identify causes of infertility, pregnancy failure and other possible causes of infertility in women.