Regulatory mechanisms of decidual gene expression linking absence of corpus luteum with preeclamptic pregnancies

黄体缺失与先兆子痫妊娠相关的蜕膜基因表达的调节机制

• 批准号: 507276351
• 负责人: Professorin Dr. Alexandra P. Bielfeld
• 金额: --
• 依托单位: Klinik für Frauenheilkunde und Geburtshilfe
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/507276351?language=en
• 关键词: Regulatory; mechanisms; decidual; gene; expression

Preeclampsia is a hypertensive disorder of pregnancy with impaired decidualization as an important contributor to the pathogenesis of the disease. Assisted reproductive technology (ART) procedures are increasingly utilized worldwide and associated with a significantly higher incidence of preeclampsia. Our recent and novel data show that this is particularly true for ART conceptions occurring in the absence of a corpus luteum (CL), e.g. in frozen embryo transfers (FET) performed in a programmed cycle. Additionally, those women who conceived without a CL exhibit impaired vascular function in early pregnancy. Interestingly, concentrations of the vasodilatory peptide hormone relaxin which is almost exclusively released by the CL in humans are undetectable in these women. How the lack of a CL and the CL hormone relaxin adds to the increased preeclampsia risk remains largely unknown and will be the focus of the proposed project. The overarching hypothesis supported by our published data and further preliminary work suggests, that the adverse maternal circulating environment in women lacking a CL induces biologic modifications which adversely affect decidualization paving the way for the development of adverse pregnancy outcomes, e.g. preeclampsia. The project will begin to close this knowledge gap by exploring how decidualization is compromised in the absence of a CL by investigating which factors impact specific gene expression changes associated with preeclampsia and how gene expression can be rescued utilizing endometrial and placental tissue as well as in vitro models. In different work packages, we will1. Compare transcriptomic profiles of decidualized endometrium derived from natural cycle FET and programmed cycle FET and to correlate the results with transcriptomic abnormalities to be known of subjects with preeclampsia.2. Determine splicing patterns and identify specific alternative splice-variants of decidualized endometrium derived from natural cycle FET and programmed cycle FET.3. Determine long-non-coding (lnc) RNAs and identify specific lnc RNA profiles of decidualized endometrium derived from natural cycle FET and programmed cycle FET. 4. Recapitulate gene expression changes in vitro, to investigate their functional consequences in HESC systems and to develop methods to restore functionality of gene expression.These data will provide novel insight into mechanisms involved in preeclampsia pathophysiology and provide the basis for the development of approaches to restore decidual homeostasis of women at risk as early as in the periconceptional period. Understanding the underlying mechanisms could ultimately lead to practical changes in clinical practice (e.g. more frequent use of protocols creating a CL or supplementation of CL products) and a reduction of adverse pregnancy outcomes which arise on the basis of a disturbed decidualization.

子痫前期是一种妊娠期高血压疾病，蜕膜受损是该病发病的重要因素。辅助生殖技术(ART)手术在世界范围内得到越来越多的应用，并与先兆子痫的发病率显著增加有关。我们最近的新数据表明，在没有黄体(CL)的情况下发生的ART受孕尤其如此，例如在程序化周期中进行的冷冻胚胎移植(FET)。此外，那些没有CL的受孕妇女在怀孕早期表现出血管功能受损。有趣的是，在这些女性身上检测不到血管扩张多肽激素松弛素的浓度，这种激素几乎只在人体内由CL释放。缺乏CL和CL激素松弛素如何增加先兆子痫的风险仍在很大程度上尚不清楚，这将是拟议项目的重点。我们已发表的数据和进一步的初步工作支持的总体假说表明，在缺乏CL的妇女中，不利的母体循环环境会诱导生物修饰，从而对蜕膜形成产生不利影响，从而为不良妊娠结局的发展铺平道路，例如先兆子痫。该项目将通过研究哪些因素影响与子痫前期相关的特定基因表达变化，以及如何利用子宫内膜和胎盘组织以及体外模型来挽救基因表达，从而开始通过探索在没有CL的情况下蜕膜如何受损来弥合这一知识鸿沟。在不同的工作包中，我们会1。比较自然周期FET和程序化周期FET的蜕膜化子宫内膜的转录转录图谱，并将结果与先兆子痫受试者已知的转录异常相关联。确定剪接模式，并确定来自自然周期FET和程序化周期FET的蜕膜子宫内膜的特定可选剪接变体。确定来自自然周期FET和程序性周期FET的蜕膜化子宫内膜的长非编码(LNC)RNA，并鉴定特定的LNC RNA图谱。4.总结基因在体外表达的变化，研究其在HESC系统中的功能后果，并开发恢复基因表达功能的方法。这些数据将为研究子痫前期的病理生理学机制提供新的见解，并为开发早期恢复高危妇女蜕膜动态平衡的方法提供基础。对潜在机制的了解最终可能导致临床实践中的实际变化(例如，更频繁地使用创建CL的方案或补充CL产品)，并减少因蜕膜紊乱而产生的不良妊娠结局。