Significance: The overall goal of Project I is to examine effects of global maternal nutrient restriction (NR), (MNR - mothers eat 70% feed eaten by ad lib controls - CTR) on placental development and function. Impairment of the placental supply line leads to fetal NR (FNR) and major obstetric problems associated with increased neonatal death and long term morbidity. Extensive rodent and sheep studies provide insight but parallel nonhuman primate (NHP) data are minimal. Hypothesis: global MNR adversely impacts key functional cellular placental mechanisms. Specifically we hypothesize that 30% MNR: 1: impairs placental development; 2: decreases placental angiogenesis; 3: decreases function of the placental IGF system; 4: impairs the placental leptin system and 5. impairs placental amino acid (AA) transport systems. We further hypothesize that there are sex and cumulative stage of development effects. Approach: We will use our group housed baboon NHP model to compare effects of MNR with CTR. This unique model was developed in the last period of funding showing continuity in the PO1. We will study 0.33, 0.5. 0.66 and 0.9 gestation (G) to determine emergence of responses to MNR at different developmental stages. We combine 1) structural, stereological; 2) biochemical - cell signaling and gene function, with global (gene arrays, proteomics) and single gene/protein (PCR and Western blot, and in situ hybridization, and immunohistochemical localization) and in vitro cell culture. MNR produces FNR, shown by decreased fetal plasma urea nitrogen, AA and IGF. Innovation: No other group uses a NHP model of MNR to evaluate effects on placental structural and functional development. These studies are not possible in human pregnancy. Environment: This project combines the skills of investigators at two Centers, University of Texas Health Science Center San Antonio, and the Southwest National Primate Research Center and all Cores. All methods are ongoing as shown by extensive preliminary data at 0.5 and 0.9G. Synergy: Similar mechanisms (IGF and nutrient sensing) are studied in all three projects and all projects use all animals. Investigators: the Pis have collaborated for a combined 85 years on the PO1 showing continuity and are joined by accomplished new investigators. In summary, this project utilizes a unique new NHP MNR model in which we already show changes in end points of our aims - fine placental structure, IGF system, and nutrient sensing. This project is now even more important because it addresses the goals of the NICHD National Children's Study which will NOT now be funded. We provide details and letters of interest to show how we will make this priceless set of tissues available to other investigators. Lay description: We pass more milestones during development in utero than any other time of our lives. Sub-optimal conditions at this time alter placental function. The placenta is key to fetal development since it is the only way the fetus obtains nutrients. Our studies will help determine mechanisms by which conditions experienced in the womb predispose to high blood pressure, obesity and diabetes in later life. Clinicians will use the information to understand optimal life style and diet for pregnant women.
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