We seek to elucidate the impact of hypoxic stress on placental differentiation and function, and consequently fetal growth. An adequate supply of proteins, carbohydrates and fat is obligatory for fetal development. Transfer of these nutrients is regulated by a set of well-orchestrated signals, programmed by genetic and environmental cues. Whereas our understanding of placental import of proteins and carbohydrates has markedly advanced in recent years, the mechanisms that govern uptake, accumulation and trafficking of fatty acids in placental trophoblasts are largely unknown and insufficiently investigated. Recent data implicate the nuclear receptor PPARy, a master regulator of adipogenesis, bioenergetics and inflammation, in regulation of placental fatty acid uptake and transport. PPARY-null mouse embryos exhibit intrauterine growth restriction and subsequently fetal death, associated with diminished fat accumulation within the labyrinthine placenta. We have recently determined that PPARy enhances trophoblast differentiation, and stimulates trophoblast uptake of fatty acids as well as the expression of proteins that govern accumulation and trafficking of fatty acids in the placenta. Importantly, environmental insults, such as exposure to hypoxia, adversely impact placental function and are associated with intrauterine death or substandard fetal growth. The mechanisms underlying these injuries are unknown. Our basic and translational research approaches are designed to understand cellular and molecular underpinnings of trophoblast fat transport and metabolism, their regulation by PPARy and the impact of hypoxic stress on these processes. We utilize novel in vivo and in vitro approaches to interrogate previously unknown gene- environment interactions that determine synthesis, utilization and efflux of fatty acids in trophoblasts, and the molecular pathways that regulate the expression and function of pertinent fatty acid transporters. We pursue feedback circuits that are instigated by free fatty acid and influence triglyceride synthesis in human trophoblasts. Together, our research will unveil previously unrecognized links between placental lipid trafficking and hypoxic injury. Consequently, our studies are likely to pave the way to better understanding of placental dysfunction that culminates in fetal growth restriction and its life-long sequelae. ? ? ?
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