With major progress in imaging modalities and Doppler flow analyses, our ability to identify fetal growth restriction (FGR) and determine its severity has markedly improved in the last twenty years. Yet the only therapeutic option to mothers with growth-restricted fetuses remains induced delivery, which is associated with prematurity and its sequelae. Surviving growth restricted neonates are at risk for cerebral palsy, growth delays, and neurobehavioral abnormalities during childhood, and for the metabolic syndrome in adulthood. Our lack of understanding of the etiology and pathobiology of FGR stands out as the major impediment on the road to cure and prevention of this common fetal disease. As the vital link between the fetus, the mother, and the environment, the placenta is essential for fetal gas exchange, transfer of nutrients, removal of waste products, hormone production, and immunological defense. It is therefore not surprising that placental dysfunction is implicated in the majority of cases of FGR that manifest in the second half of pregnancy. A common pathway that leads to FGR is reduced placental perfusion, resulting in decreased nutrient supply, cellular hypoxia and an increased rate of placental cell death. Yet a missing piece in the puzzle is the link between abnormal placental perfusion and substandard supply of metabolic fuels to the developing fetus. This proposal centers on the supply of fatty acids across the trophoblast and into the fetal capillaries, where they provide a critical source of calories and fulfill the need of the developing fetal nervous system for selected polyunsaturated fatty acids. Whereas storage of fat in the form of triacylglycerols is seen in other cell types that amass fat, such as adipocytes, the trophoblast is unique in its ability to regulate storage and efflux of fatty acids between two distinct blood systems. Importantly, perturbations to this trafficking process have dire consequences to both the placenta and the fetus, leading to reduced supply of essential metabolic fuels to the fetus while accumulating lipotoxic substrates in the placenta. Trophoblast lipotoxicity may damage the already dysfunctional placenta, further compromising fetal growth, which culminates in clinical FGR. In this proposal, we seek to define key pathways in placental lipid storage and mobilization, and decipher the mechanistic basis of trophoblastic lipid lipotoxicity. Using LC/ESI-MS high-throughput lipidomics, we will interrogate the function of proteins that support trophoblastic lipid droplets and fatty acid efflux. We will buttress our investigation into the mechanisms of lipotoxicity with innovative approaches for imaging mass spectrometry for in situ lipidomics. We will also examine novel PPAR? signaling pathways that may mitigate lipotoxicity. Together, our original questions, bolstered by enabling technologies, constitute a novel approach to placental injury, and will illuminate previously unknown pathways that underlie placental adaptation to injury and its sequelae.
The proposal detailed here centers on placental lipid mobilization, which plays a pivotal role in placental metabolism and the regulation of fetal nutrition. We will analyze the mechanism of lipid accumulation within the placenta to glean information on placental damage. Our research will illuminate new pathways that may serve to improve placental function and consequently, fetal and child health.
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