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. !

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD071100-02
Application #
8446277
Study Section
Pregnancy and Neonatology Study Section (PN)
Program Officer
Ilekis, John V
Project Start
2012-04-01
Project End
2017-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
2
Fiscal Year
2013
Total Cost
$305,223
Indirect Cost
$108,305
Name
University of California San Diego
Department
Pathology
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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
Li, Yingchun; Parast, Mana M (2014) BMP4 regulation of human trophoblast development. Int J Dev Biol 58:239-46
Li, Yingchun; Moretto-Zita, Matteo; Soncin, Francesca et al. (2013) BMP4-directed trophoblast differentiation of human embryonic stem cells is mediated through a ýýNp63+ cytotrophoblast stem cell state. Development 140:3965-76
Tache, Veronique; Ciric, Aleksandar; Moretto-Zita, Matteo et al. (2013) Hypoxia and trophoblast differentiation: a key role for PPARýý. Stem Cells Dev 22:2815-24