Melatonin: functions and mechanisms of action in placental trophoblast

在过去的九年里，我们的研究项目得到了nserc发现基金的资助，证明了褪黑激素及其受体在胎盘功能中的重要作用。褪黑素是一种多相作用的分子，具有非常大的功能。过去十年的研究表明，褪黑素对周围生殖器官具有前所未有的有益作用，其中一个很可能与它消除氧化应激和胎盘功能障碍的能力有关。我们之前的研究表明，褪黑素在胎盘中大量产生，它可以防止氧化应激引起的分子损伤和细胞功能障碍。**本研究计划是我们正在进行的nserc支持项目的直接延伸，建立在近期进展的基础上，通过确定短期目标和长期目标，了解褪黑激素在母胎界面、胎盘中的作用，并建立细胞模型来研究这种吲哚胺的调节和保护功能。未来5年的短期目标是阐明褪黑素保护绒毛滋养细胞免受缺氧/再氧化引起的损伤的机制。具体来说，在胎盘绒毛滋养细胞中，我们将剖析褪黑激素对缺氧/再氧化诱导的线粒体（内在）凋亡和氧化应激的保护机制；并确定褪黑激素是否调节自噬，并防止缺氧/再氧诱导的内质网应激和线粒体功能障碍。我们的研究项目，利用滋养细胞，使用新的方法来发现褪黑素发挥促生存和细胞保护作用的机制。同时，毫无疑问，拟议的研究与胎盘健康特别相关，从而与妊娠健康和胎儿发育有关。拟议研究的结果将引起广泛社区的兴趣，从胎盘学家到神经学家，药理学家和细胞生物学家。总的来说，拟议的研究计划将推进我们对褪黑激素及其受体在滋养细胞中的保护作用的基础知识，以及它在正常和异常细胞过程（例如神经发育，抑郁症，癌症和心血管疾病）中的作用，并为这些领域的新预防和治疗方法的发展开辟道路。褪黑素已被建议用于多种疾病的潜在治疗，包括产科并发症、抑郁症、癌症和神经退行性疾病。

Over the past nine years, our research program funded by NSERC-discovery grant has allowed demonstrating a crucial role of melatonin and its receptors in placental function. Melatonin is a heterogeneously-acting molecule with an exceptionally large skill set. Research within the last decade has shown melatonin to have previously-unsuspected beneficial actions on the peripheral reproductive organs, one of which very likely relates to its ability to obviate oxidative stress and placental dysfunction. We previously shown that melatonin is highly produced in the placenta where it protects against molecular damage and cellular dysfunction arising from oxidative stress. **This research proposal, which is a direct extension of our ongoing NSERC-supported program, builds on recent progress by identifying short-term goals with the long-term aim of understanding the role of melatonin at the maternal-fetal interface, the placenta, and to develop a cellular model to study the regulation and protective function of this indolamine. The short-term goals of the next 5 years is to elucidate the mechanisms by which melatonin protects the villous trophoblast against hypoxia/reoxygenation-induced damage. Specifically, in placental villous trophoblast cells, we will dissect the mechanism underlying melatonin protective on hypoxia/reoxygenation-induced mitochondrial (intrinsic) apoptosis and oxidative stress; and determine if melatonin regulates autophagy and protects against hypoxia/reoxygenation-induced endoplasmic reticulum-stress and mitochondrial dysfunction. Our program of research, using trophoblast cell, uses novel approaches to discover the mechanisms by which melatonin plays a pro-survival and cytoprotective role. At the same time there is no doubt that the proposed studies are particularly relevant for placental health and, by consequence for pregnancy well-being and fetal development. The findings of the proposed research will be of interest to a broad community, from the placentologist to the neurologist, pharmacologist and cellular biologist. Collectively, the proposed research program will advance our fundamental knowledge of the protective role of melatonin and its receptors in trophoblast cells as well as its role in normal and abnormal cellular processes (e.g. neurodevelopment, depression, cancer, and cardiovascular diseases) and open the way for the development of new preventive and therapeutic approaches in these areas. Melatonin has been suggested for the potential treatment of a variety of disorders, including obstetric complications, depression, cancer, and neurodegenerative disease.