The Dynamic Role of the Oxygen/TGFß Axis in Regulating Sphingolipid Metabolism during Placental Development

***生长中的胎盘所经历的氧张力变化对于婴儿在母体子宫内的正常发育至关重要，当缺氧环境持续超过妊娠前三个月时，它将导致胎盘发育和功能不适当。在过去的几十年里，在老鼠身上进行的研究发现，在怀孕期间控制氧稳态的分子的遗传操纵经常导致胚胎死亡，并且经常与胎盘的惊人异常有关。然而，对胎盘的观察大多是描述性的，这些基因操作对胎盘细胞死亡的贡献仍然难以捉摸，胎盘细胞死亡是胎盘器官正常生长所必需的事件。在这个项目中，我们假设氧张力的变化通过转化生长因子ß3 （TGFß3）的激活来调节发育中的胎盘中生物活性鞘脂的代谢。我们提出了一种综合的方法，利用相关的小鼠模型和最先进的脂质组学分析来定义氧气通过生物活性鞘脂控制胎盘细胞死亡和存活的精确机制。长期目标是开发早期诊断探测器以及基于证据的干预计划，以预防妊娠并发症。该项目在许多方面具有独特性和创新性：1)没有关于小鼠妊娠期鞘脂表达/功能的氧依赖机制的信息；本文提出了一种新的鞘脂代谢调控途径。2)我们也是第一个研究鞘脂在小鼠胎盘细胞命运调节中的功能，这是一个仍然难以捉摸的研究领域。研究鞘脂变化/功能的新方法不仅将推动妊娠研究领域的发展，也将推动其他研究领域的发展。确定胎盘鞘脂代谢的控制机制将提高我们对该器官发育中的氧信号和调控的理解，并改善胚胎发育的健康状况。这可能最终改善对怀孕的管理，并防止母亲及其后代在以后的生活中患上相关疾病的风险。**

***Changes in oxygen tension experienced by the growing placenta are crucial for proper development of the baby in the maternal womb and when a hypoxic environment persists beyond the first trimester of gestation, it consequently leads to inappropriate placental development and function. In the past decades, studies conducted in mouse have found that genetic manipulation of molecules that control oxygen homeostasis during pregnancy often leads to embryonic death and is frequently associated with striking abnormalities of the placenta. However, placental observations have been mostly descriptive and contribution of these genetic manipulations on placental cell death, an event required for proper growth of this organ, remains elusive. In this project we hypothesize that change in oxygen tension via activation of Transforming Growth Factor ß3 (TGFß3) regulate the metabolism of bioactive sphingolipids in the developing placenta. We propose an integrated approach utilizing relevant murine models and state-of-the-art lipidomic analyses to define the precise mechanism(s) of oxygen control of placental cell death and survival via bioactive sphingolipids. The long-term objective is to develop early diagnostic detectors as well as evidence-based intervention plans to prevent complication of pregnancy. The project is unique and innovative in many aspects: 1) No information is available on the oxygen-dependent mechanism(s) influencing the expression/function of sphingolipids in mouse pregnancy; in the current proposal we put forward a novel pathway of sphingolipid metabolism regulation. 2) We are also the first to examine the function of sphingolipids in the regulation of mouse placental cell fate, a research area that remains elusive. The proposed new methodological approaches to examine sphingolipid changes/function will not only advance the research field of pregnancy but also those of other research areas. Defining the controlling mechanisms of sphingolipid metabolism in the placenta will improve our understanding of oxygen signaling and regulation in the development of this organ and the well-being of the developing embryo. This may ultimately improve the management of pregnancy and prevent the risk of developing associated illnesses later in life both in mothers and their offspring. **