Human Endometrial Nitric Oxide: Regulation and Function

说明(申请人提供)：一氧化氮(NO)是一种自由基，具有 多种生理功能，其中之一就是它的平滑肌松药 效果。通过这种作用，一氧化氮在调节血管功能中起着关键作用。 音调因此为1：流向许多器官，包括生殖道。 内皮型一氧化氮合酶的最新鉴定 (ENOS)在人子宫中，主要定位于子宫内膜腺 提出了这种分子可能具有其他功能的可能性 调节血流，如控制子宫内膜腺分泌。 此外，子宫内膜enos mRNA表达显著增加。 和蛋白质在植入前的预期时间附近有所下降 月经提示子宫内膜eNOS受性类固醇调节， 在植入过程中起作用。在本提案中，我们将测试 性激素调控子宫内膜eNOS和NO的假说 发挥雌激素对细胞增殖的影响的中介作用， 孕酮在子宫内膜蜕膜化诱导中的作用测试我们的 假设我们将使用体外方法使用原代人类来源的 检测雌孕激素对子宫内膜细胞的直接作用 联合应用对eNOS表达和NO分泌的影响(特异靶1) 阻断子宫内膜NO合成的药理工具，以及 转染研究上调eNOS基因表达我们将确定是否 NO介导E和P在子宫内膜的作用或不依赖性激素 对蜕膜细胞增殖和子宫内膜分泌的影响 产品(具体目标2和3)。为了补充这些研究，我们将使用 体外方法确定植入失败的患者是否可能 子宫内膜内皮型一氧化氮合酶缺陷症的特异性目标4)。这项初步研究应该会给我们带来一些启示 人子宫内膜NO通路的调节和功能 研究领域具有深远的临床意义。

DESCRIPTION (Provided by Applicant): Nitric oxide (NO) is a free radical with diverse physiological functions one of which is its smooth muscle relaxant effects. By virtue of this effect NO plays a key role in regulating vascular tone and therefore 1: flow to many organs including the reproductive tract. Recent identification of predominantly endothelial nitric oxide synthese (eNOS) in the human uterus with primary localization to the endometrial glands has raised the possibility that this molecule may have functions other than regulation of blood flow, such as control of endometrial glandular secretion. Additionally, the marked increase in the endometrial expression of eNOS mRNA and protein around the expected time of implantation with a decline just prior menstruation suggests that endometrial eNOS is regulated by sex steroids, and plays a role in implantation process. In this proposal we will test the hypothesis that sex hormones regulate endometrial eNOS, and NO in turn functions as a mediator of estrogenic influence on cellular proliferation, progesterone's effect in induction of endometrial decidualization. To test our hypothesis we will use in vitro approach using primary human derived endometrial cells to test the direct effects of estrogen progesterone and their combination on eNOS expression and NO secretion (Specific Aim 1) Using pharmacological tools to block the synthesis of endometrial NO, and transfection studies to upregulate eNOS gene expression we will determine if NO mediates E and P actions in the endometrium or independent of sex steroids influence cellular proliferation and endometrial secretion of decidual products (Specific Aims 2 and 3). To complement these studies we will use an ex vivo approach to determine if patients with implantation failures may have endometrial eNOS defects Specific Aim 4). This pilot study should shed light on regulation and function of human endometrial NO pathway, an uninvestigated area of research with profound clinical significance.