Modulation of the Receptive Endometrium by CG

描述（由申请人提供）：妊娠的开始需要子宫内膜发育和植入囊胚之间精确的定时同步。这个“接受窗口”最初依赖于雌激素和孕激素。然而，来自发育中的胚胎的信号进一步改变了接受性子宫。在上一个资助期间，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，除了在接受性窗口期间由雌激素和孕激素诱导的特定变化外，以模拟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。在所有三种主要细胞类型中变化是明显的，即，腔上皮、腺上皮和间质成纤维细胞。CG直接作用于子宫内膜，独立于卵巢，调节基质成纤维细胞的细胞骨架结构和腺上皮细胞分泌活性的增加。此外，当孕酮受体被拮抗时，这些反应被抑制。由于我们的体内研究已经清楚地表明了CG对调节子宫容受性的直接影响，我们现在提出了一系列的研究，以确定两个基因产物的功能，诱导基质成纤维细胞在CG刺激。基质细胞蛋白（SCP）和Notch-1均在基质细胞中表达，并且它们的表达在体内和体外均由CG调节。第一个特定目的是确定SCP激活免疫细胞中的增殖激活基因的机制，这反过来可能导致子宫内膜内淋巴细胞群体的表型改变。我们推测这些调节机制在提供胎儿同种异体移植免疫耐受中起着重要作用。在第二个具体目标中，我们提出确定Notch-1抑制基质成纤维细胞凋亡的作用。此外，Notch-1还能够影响淋巴谱系内表型分化的定型。因此，这些研究将提供深入了解的机制，基质成纤维细胞在建立怀孕过程中发挥重要作用。了解妊娠早期子宫环境中复杂的免疫和细胞分化机制，与我们识别不孕症、妊娠失败和其他可能导致女性不孕症的原因的能力直接相关。

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.