Cell differentiation during decidualization

蜕膜化过程中的细胞分化

• 批准号: 6873394
• 负责人: ZUZANA STRAKOVA
• 金额: $ 27.9万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-12-01 至 2008-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6873394
• 关键词: baboons; biological signal transduction; cell cycle; cell differentiation; cell transformation; clinical research; cyclin dependent kinase; cytoskeleton; decidua; enzyme activity; fibroblasts; human tissue; interleukin 1; mitogen activated protein kinase; placenta; pregnancy; progesterone; stromal cells

DESCRIPTION (provided by applicant): Decidualization, which involves the differentiation of the uterine stomal fibroblasts to decidual cells, is a major change that occurs in the primate endometrium after conception and is critical for the establishment and maintainance of pregnancy. The events leading to this cellular change at the biochemical and molecular level have yet to be fully explored. In vivo studies demonstrated that conceptus is essential to regulate this process in the primate. Based on our studies in baboon and human stromal fibroblasts the cytokine interleukin-1 (1L-1) was established as one of the possible mediators of decidualization. In specific aim 1 we propose to study novel non-genomic signal transduction pathways induced by progesterone and determine whether progesterone interacts with IL-1 induced signal to regulate mitogen activated protein kinases. We propose that these pathways are critical during the initiation of decidualization in human and baboon stromal fibroblasts. The changes induced by progesterone in synergy with an embryonic signal lead to cytoskeletal reorganization and cell transformation. In specific aim 2 we propose to investigate whether manipulation of the mechanical characteristics of cytoskeleton leading to its stabilization will prevent the decidualization process. We hypothesize that as result of cytoskeletal reorganization, cells exit their cell cycle, which allows them to differentiate. A cell cycle kinase important for the exit from the cell cycle, cyclin dependent kinase 4 (cdk4), is downregulated during in vivo and in vitro decidualization. Therefore, in specific aim 3 we will examine the possible mechanisms leading to cdk4 regulation and determine how manipulation of cdk4 expression will affect decidualization. It is our hope that the knowledge gained from our studies in the non-human primate and human stromal cells could contribute to therapies for diseases connected with decidualization defects. These may include endometrial dysfunction associated with infertility, pregnancy failures in patients with luteal phase defects, habitual abortions and/or insufficient placental development.

描述（由申请人提供）：deDIDAILIAD，涉及子宫固有成纤维细胞与判决细胞的分化，是受孕后灵长类化子宫内膜发生的一个重大变化，对于妊娠的建立和维持至关重要。在生化和分子水平上导致这种细胞变化的事件尚未充分探索。体内研究表明，概念对于在灵长类动物中调节这一过程至关重要。基于我们在狒狒和人基质成纤维细胞中的研究，细胞因子白介素-1（1L-1）被确定为可能的decIDAILAIDE介质之一。在特定目标1中，我们建议研究由孕酮诱导的新型非基因组信号转导途径，并确定孕酮是否与IL-1诱导的信号相互作用以调节有丝分裂原活化蛋白激酶。我们建议这些途径在人和狒狒基质成纤维细胞的de义化过程中至关重要。与胚胎信号的协同作用中孕激素诱导的变化导致细胞骨架重组和细胞转化。在特定的目标2中，我们建议调查对导致其稳定的细胞骨架的机械特征的操纵是否会防止斜进过程。我们假设，由于细胞骨架重组的结果，细胞退出了细胞周期，从而使它们能够区分。细胞周期激酶对于从细胞周期出口至关重要的细胞周期依赖性激酶4（CDK4）在体内和体外deDIDAILIAD期间被下调。因此，在特定的目标3中，我们将检查导致CDK4调控的可能机制，并确定CDK4表达的操纵将如何影响切除。我们希望我们从非人类灵长类动物和人类基质细胞的研究中获得的知识可以促进与de骨缺陷有关的疾病的疗法。这些可能包括与不育相关的子宫内膜功能障碍，黄体相缺陷患者的妊娠失败，习惯流产和/或胎盘发育不足。