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

先兆子痫是妊娠期高血压疾病，蜕膜化受损是疾病发病机制的重要因素。辅助生殖技术（ART）程序在世界范围内越来越多地使用，并与先兆子痫的发病率显着升高有关。我们最近的新数据表明，这对于在没有黄体（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，那些怀孕时没有CL的妇女在怀孕早期表现出血管功能受损。有趣的是，在这些女性中检测不到几乎完全由CL释放的血管舒张肽激素松弛素的浓度。缺乏CL和CL激素松弛素如何增加先兆子痫的风险仍然是未知的，这将是拟议项目的重点。由我们发表的数据和进一步的初步工作支持的总体假设表明，缺乏CL的女性的不良母体循环环境诱导生物学修饰，其对蜕膜化产生不利影响，为不良妊娠结局的发展铺平了道路，例如先兆子痫。该项目将开始通过研究哪些因素影响与先兆子痫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挽救基因表达来探索在没有CL的情况下蜕膜化如何受损，从而缩小这一知识差距。在不同的工作包中，我们将1. 比较自然周期FET和程序周期FET的蜕膜化子宫内膜的转录组学特征，并将结果与先兆子痫受试者已知的转录组学异常相关联。 确定自然周期FET和程序周期FET来源的蜕膜化子宫内膜的剪接模式和识别特定的选择性剪接变体。 确定长链非编码（lnc）RNA，并确定来自自然周期FET和程序周期FET的蜕膜化子宫内膜的特异性lnc RNA谱。4. 概括基因表达的变化在体外，研究其功能的后果在HESC系统和开发方法，以恢复功能的基因express.These数据将提供新的见解先兆子痫的病理生理学机制，并提供基础的发展方法，以恢复蜕膜稳态的妇女风险早在围受孕期。了解潜在的机制可能最终导致临床实践的实际变化（例如，更频繁地使用创建CL或补充CL产品的方案），并减少由于蜕膜化紊乱而引起的不良妊娠结局。

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.