Melatonin: functions and mechanisms of action in placental trophoblast

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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.