Fetal growth disorders (both growth restriction and overgrowth) are common pregnancy complications, which carry an increased risk of adverse outcomes in the perinatal period and an increased risk of development of adult disease, including diabetes and cardiovascular disease. The placenta is a fetal-derived organ, whose proper development and function are pivotal in pregnancy success. Trophoblastic cells comprise the epithelial compartment of the placenta, and mediate nutrient/gas exchange functions and establishment of maternal blood flow into the feto-placental unit. Abnormal fetal growth has been associated with disorders of trophoblastic differentiation and function during early events in placentation, which lead to chronic feto-placental hypoxia. PPARgamma, a ligand-activated transcription factor and target of the thiazolidinedione family of anti-diabetic drugs, and Sirt1, a protein deacetylase and negative regulator of PPARgamma, have previously been shown to be involved in multiple facets of cell and tissue function, including differentiation nutrient-sensing, and metabolism. We have shown that Sirt1-PPARgamma signaling is specifically involved in trophoblast differentiation and hypoxia-induced trophoblast injury. In addition, both Sirt1-knockout and PPARgamma overstimulation have been shown to cause fetal growth restriction in mice. Finally, in human placentas, the expression and/or activity of PPARgamma and its endogenous ligands are altered in placentas associated with abnormal fetal growth, including fetal growth restriction, preeclampsia, and gestational diabetes. The goal of this proposal is to determine the mechanisms by which Sirt1-PPARgamma signaling contribute to trophoblastic differentiation, hypoxia-induced placental injury, and placenta-based fetal growth disorders. This project has the potential to identify therapeutic targets for these diseases, leading to a decrease in perinatal morbidity and mortality.

Public Health Relevance

Fetal growth disorders, including growth restriction and macrosomia, are common pregnancy complications, which carry an increased risk of adverse outcomes in the perinatal period and development of adult disease, including diabetes and cardiovascular disease. This project explores mechanisms by which one particular signaling pathway in the placenta contributes to fetal growth, focusing on potential therapeutic targets which could improve fetal well-being. !

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Study Section
Pregnancy and Neonatology Study Section (PN)
Program Officer
Ilekis, John V
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University of California San Diego
Schools of Medicine
La Jolla
United States
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Arul Nambi Rajan, Kanaga; Khater, Marwa; Soncin, Francesca et al. (2018) Sirtuin1 is required for proper trophoblast differentiation and placental development in mice. Placenta 62:1-8
Pham, Jonathan; Arul Nambi Rajan, Kanaga; Li, Ping et al. (2018) The role of Sirtuin1-PPAR? axis in placental development and function. J Mol Endocrinol 60:R201-R212
Soncin, Francesca; Khater, Marwa; To, Cuong et al. (2018) Comparative analysis of mouse and human placentae across gestation reveals species-specific regulators of placental development. Development 145:
Chang, Ching-Wen; Wakeland, Anna K; Parast, Mana M (2018) Trophoblast lineage specification, differentiation and their regulation by oxygen tension. J Endocrinol 236:R43-R56
Wakeland, Anna K; Soncin, Francesca; Moretto-Zita, Matteo et al. (2017) Hypoxia Directs Human Extravillous Trophoblast Differentiation in a Hypoxia-Inducible Factor-Dependent Manner. Am J Pathol 187:767-780
Chang, Ching-Wen; Parast, Mana M (2017) Human trophoblast stem cells: Real or not real? Placenta 60 Suppl 1:S57-S60
Horii, Mariko; Li, Yingchun; Wakeland, Anna K et al. (2016) Human pluripotent stem cells as a model of trophoblast differentiation in both normal development and disease. Proc Natl Acad Sci U S A 113:E3882-91
Horii, Mariko; Moretto-Zita, Matteo; Nelson, Katharine K et al. (2015) MTA3 regulates differentiation of human cytotrophoblast stem cells. Placenta 36:974-80
Moretto Zita, Matteo; Soncin, Francesca; Natale, David et al. (2015) Gene Expression Profiling Reveals a Novel Regulatory Role for Sox21 Protein in Mouse Trophoblast Stem Cell Differentiation. J Biol Chem 290:30152-62
Soncin, Francesca; Natale, David; Parast, Mana M (2015) Signaling pathways in mouse and human trophoblast differentiation: a comparative review. Cell Mol Life Sci 72:1291-302

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