The mechanisms linking matemal nutrient restriction to reduced fetal growth and programming of adult disease remain to be fully established. We have proposed that the placenta functions as a nutrient sensor, regulating placental nutrient transporters, and therefore fetal growth, in response to changes in the ability of the matemal supply line to deliver nutrients to the placenta. We will test the central hypothesis that inhibition of placental insulin/IGF-l, leptin and mTOR signaling constitute a key molecular link between maternal nutrient restriction, reduced fetal growth and fetal programming by downrregulatlon of placental nutrient transporters, which limits fetal supply of amino acids and methyl donors. We will study matemal nutrient restriction (IVINR, -^30% nutrient intake) in pregnant baboons. Placentas from control and MNR baboons will be studied at two gestational ages (GD 140 and 180).
In Aim 1, we will determine the effect of MNR on matemal metabolism, placental signaling and protein synthesis. We will measure maternal hormone, adipokine and nutrient levels and placental insulin/IGpTl, leptin, mTOR, AMPK, GCN2, and GSK3 signaling. Synthesiis of specific proteins will be determined by quantitative proteomics using Stable Isotope Labeling with Amino acids in Culture (SILAC), dimethyl labeling and LC-MS/MS.
In Aim 2 the impact of MNR on placental transport and fetal serum concentrations of nuti-ients and methyl donors will be established. The activity and protein expression of transporters for glucose, amino acids and methyl donors (folate, vitamin B12) will be determined in syncytiotrophoblast plasma membranes. In vivo transplacental transport of amino acids will be measured using stable isotopes. In both Aim 1 and 2, we will use high throughput discovery approaches (Next Gen sequencing) to discover additional and novel placental signaling pathways and transporters regulated by MNR.
In Aim 3 we will determine the role of leucine and placental mTOR signaling in linking MNR to decreased placental nutrient transport and reduced fetal growth. MNR animals will be Supplemented with leucine from GD 30. The activity and expression of placental mTOR signaling and transporters for glucose, amino acids and metiiyl donors, and fetal nutrient levels and growth will be determined. Significance: Matemal under nutrition is a serious public health problem in the US and worldwide. This work will explore the molecular mechanisms linking MNR to altered placental function and reduced fetal growth in the non-human primate. Innovation: The placental nutrient sensing hypothesis is conceptually novel and challenges the traditional view of how placental function is regulated.
Maternal under nutiition during pregnancy remains a daunting problem worldwide and more than 50 million Americans live in households experiencing food insecurity or hunger. We will explore the mechanisms linking matemal nutrient restriction to altered placental function and reduced fetal growth in the non^human primate. It is expected that this knowledge will improve our understanding of the causes underlying common pregnancy complications and may allow the development of novel treatment strategies.
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