Cytoskeletal regulation of the Hippo and Notch1 signaling pathways in endometrial stromal cell decidualization and endometriosis

子宫内膜基质细胞蜕膜化和子宫内膜异位症中 Hippo 和 Notch1 信号通路的细胞骨架调节

• 批准号: 10385956
• 负责人: Genna Moldovan
• 金额: $ 3.87万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10385956
• 关键词: Actins; Address; Affect; Age; Basic Science; Cells; Cellular Morphology; Cellular biology; Cyclic AMP; Cytoskeleton; Decidual Cell Reactions; Defect; Development; Disease; Dysmenorrhea; Embryo; Endometrial; Endometrial Stromal Cell; Enzymes; Failure; Female infertility; Focal Adhesion Kinase 1; Functional disorder; Human; Human Chorionic Gonadotropin; Impairment; Infertility; Interleukin-1 beta; Knowledge; Lead; Ligands; Luteal Phase; Mediating; Molecular; Molecular Biology; Morphology; Myosin ATPase; Myosin Light Chain Kinase; NOTCH1 gene; Notch Signaling Pathway; Pathology; Pathway interactions; Pelvic Pain; Phosphorylation; Phosphotransferases; Play; Pregnancy; Process; Progesterone; Proteins; Regulation; Reproductive Process; Research; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Site; Smooth Muscle Actin Staining Method; Stromal Cells; Structure; Technical Expertise; Testing; Tissues; Vinculin; Woman; career; cell transformation; diagnostic biomarker; endometriosis; eutopic endometrium; experience; insight; member; notch protein; novel; programs; protein protein interaction; reproductive; reproductive success; response; skills; steroid hormone; success; trafficking

PROJECT SUMMARY Endometrial stromal cell decidualization is critical to reproductive success. The decidualization process involves morphological and functional changes of endometrial stromal cells. The actin-myosin cytoskeleton contributes to changes in cell morphology and likely plays a role in the intracellular shuttling of proteins critical in decidualization. Decidualization is the terminal differentiation of human endometrial stromal cells in response to rising progesterone levels and is maintained throughout pregnancy by embryonic signals and progesterone. Defects in this process are associated with reproductive failure in diseases such as endometriosis. Endometriosis is characterized by endometrial-like tissue found at ectopic sites and the disease is associated with significant pelvic pain, infertility, and dysmenorrhea, but its pathophysiology remains elusive. The aim of this proposal is to understand the functional role of the cytoskeleton in the decidualization process and determine how this is aberrant in the stromal cells of women with endometriosis which may contribute to their infertility. The Hippo target homologs, YAP and TAZ, and Notch1 signaling are known to mediate the initiation of the decidualization response, but what regulates these pathways during decidualization remains unknown. Previous research has also shown that significant changes in the cytoskeleton are associated with endometrial stromal cell decidualization. In addition, cytoskeleton dynamics and Notch1 and YAP/TAZ signaling are dysregulated in endometriosis. We hypothesize that the cytoskeleton mediates the decidualization response and is defective in infertile women with endometriosis. To test our overall hypothesis in Aim 1 we will investigate direct actin-myosin cytoskeleton regulation of the Hippo/YAP/TAZ and NOTCH1 signaling pathways in the context of endometrial stromal cell decidualization and in Aim 2, we will determine how an altered cytoskeleton compromises decidualization in stromal cells from infertile women with endometriosis. The proposed studies will address cytoskeletal regulation of key molecular mechanisms that regulate stromal cell decidualization. These studies will greatly expand the technical expertise in cell and molecular biology of the applicant. These experiences combined with professional development supported by the sponsor, co-sponsor, and program will help the applicant to develop the skill set required to pursue a career in basic science research.

项目概要 子宫内膜基质细胞蜕膜化对于生殖成功至关重要。蜕膜化过程包括 子宫内膜基质细胞形态和功能的变化。肌动蛋白-肌球蛋白细胞骨架有助于 细胞形态的变化，并可能在细胞内穿梭中发挥重要作用 蜕膜化。蜕膜化是人子宫内膜基质细胞响应于 黄体酮水平升高，并在整个怀孕期间通过胚胎信号和黄体酮维持。 这一过程的缺陷与子宫内膜异位症等疾病的生殖障碍有关。 子宫内膜异位症的特征是在异位部位发现子宫内膜样组织，该疾病与 伴有明显的盆腔疼痛、不孕和痛经，但其病理生理学仍然难以捉摸。此举的目的 建议是了解细胞骨架在蜕膜化过程中的功能作用并确定 患有子宫内膜异位症的女性的基质细胞出现这种异常，可能导致她们不孕。这 已知 Hippo 靶标同源物 YAP 和 TAZ 以及 Notch1 信号传导可介导 蜕膜化反应，但在蜕膜化过程中调节这些途径的因素仍然未知。以前的 研究还表明，细胞骨架的显着变化与子宫内膜间质有关 细胞蜕膜化。此外，细胞骨架动力学以及 Notch1 和 YAP/TAZ 信号在 子宫内膜异位症。我们假设细胞骨架介导蜕膜化反应并且在以下方面存在缺陷： 患有子宫内膜异位症的不孕妇女。为了检验我们在目标 1 中的总体假设，我们将研究直接肌动蛋白-肌球蛋白 子宫内膜背景下 Hippo/YAP/TAZ 和 NOTCH1 信号通路的细胞骨架调节 基质细胞蜕膜化，在目标 2 中，我们将确定改变的细胞骨架如何妥协 患有子宫内膜异位症的不孕女性基质细胞的蜕膜化。拟议的研究将解决 细胞骨架对调节基质细胞蜕膜化的关键分子机制的调节。这些研究 将极大地扩展申请人在细胞和分子生物学方面的技术专长。这些经历 与赞助商、共同赞助商和项目支持的专业发展相结合将有助于 申请人培养从事基础科学研究职业所需的技能。