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分压变化对婴儿在母体子宫中的正常发育至关重要，当低氧环境持续到怀孕前三个月后，就会导致胎盘发育和功能不适当。在过去的几十年里，在小鼠身上进行的研究发现，在怀孕期间对控制氧气稳态的分子进行基因操作往往会导致胚胎死亡，并经常与胎盘的显著异常有关。然而，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，我们假设氧分压的变化是通过激活转化生长因子β3(转化生长因子3)来调节发育中的胎盘中具有生物活性的鞘磷脂的代谢。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肪组学分析来确定氧通过生物活性鞘磷脂控制胎盘细胞死亡和存活的精确机制(S)。长期目标是开发早期诊断探测器和循证干预计划，以预防妊娠并发症。该项目在许多方面具有独到之处和创新性：1)目前还没有关于氧依赖机制(S)影响小鼠妊娠中鞘磷脂表达/功能的信息；在本提案中，我们提出了一条新的鞘磷脂代谢调节途径。2)我们还首次研究了鞘磷脂在调节小鼠胎盘细胞命运中的作用，这是一个仍然难以捉摸的研究领域。提出的检测鞘脂变化/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。明确胎盘鞘磷脂代谢的调控机制将有助于我们更好地理解氧在该器官发育和胚胎发育过程中的信号和调控。这可能最终改善对怀孕的管理，并防止母亲及其子女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. **