The role of oxysterols in placental biology

Magee-Women'S Res Inst And Foundation, Pittsburgh PA

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Abstract

? DESCRIPTION (provided by applicant): Fetal growth restriction (FGR) is associated with increased risk of intrauterine and neonatal death, as well as adverse health outcomes from infancy through adulthood. Yet pathways that link specific biologic insults to FGR remain obscure. Formation of oxysterols, the products of cholesterol oxidation, is promoted by oxidative stress and hypoxia, common insults germane to FGR. Indeed, levels of oxidized cholesterol species are increased in the maternal, fetal and placental compartments of pregnancies affected by FGR. LXR and SREBP2 are key transcriptional regulators of cellular lipid homeostasis, potently regulated by oxysterols. We have previously shown that elevated concentrations of oxysterols inhibit differentiation and progesterone synthesis, while inducing cell toxicity in term primary human trophoblasts. Outside of pregnancy, targeted manipulation of LXR and SREBP2-regulated transcriptional pathways has been shown to alleviate toxicity stemming from oxysterol exposure as well as hypoxia, dyslipidemia, and ischemia/reperfusion. However, the role that oxysterols play in placental biology remains incompletely understood. We hypothesize that the oxidation of cholesterol is a critical mediator of metabolic dysregulation and placental dysfunction stemming from hypoxic injury and oxidative stress. We aim to test this hypothesis, and to determine if pathways regulated by LXR or SREBP2 can be targeted to ameliorate placental dysfunction caused by hypoxic injury or oxidative stress. Complementing in vitro analysis of primary human trophoblasts with work in live mice, we will target LXR and SREBP2 using pharmacologic, endocrine and genetic manipulations to dissect mechanistic pathways that determine the effects of cholesterol oxidation on placental biology. Moreover, we will probe the role of cholesterol oxidation in potentiating the placental sequelae of hypoxia and oxidative stress, and query potential therapeutic targets for the alleviation of toxicity stemming from these biologic insults. This work will address critical gaps in the understanding of underlying causes of placental injury and dysfunction, and is likely to uncover targetable pathways to alleviate the pathophysiology of FGR.