Significance: The overall PO1 goal PO1 is to study effects of global maternal (M) nutrient restriction (NR), (MNR - mothers eat 70% feed eaten by ad lib controls (CTR). Sub-optimal fetal (F) organ growth and development are major problems associated with increased neonatal death and long term morbidity. Underlying mechanisms are poorly understood. Whilst primary causes are diverse, poor F development is generally secondary to F NR. Rodent and sheep studies provide insight but parallel nonhuman primate (NHP) data are minimal. Hypothesis: exposure of baboons to MNR adversely impacts growth and key cellular processes in placenta, F brain and F kidney. We hypothesize: 30% global MNR: 1: impairs growth;2: impairs angiogenesis;3: impacts the IGF system;4: alters cellular nutrient sensing;5. influences programmed cell death, in an F sex and developmental stage specific manner. Approach: We use a 30% global MNR baboon model housed in groups to compare MNR with TR mechanisms. Projects evaluate I) placenta, II) F brain and III) F kidney effects of MNR at 0.33, 0.5. 0.66 and 0.9 gestation (G) to determine cumulative outcomes. We combine 1) stereological;2) biochemical - cell signaling and gene function, with global (gene arrays, proteomics) and candidate gene/protein (PCR, in situ hybridization, Western blot and immunohistochemistry) and in vitro (matrigel) and 3) in vivo approaches. Innovation: Our preliminary data show that 30% MNR produces F NR (decreased F blood urea nitrogen, amino acids and growth factors). No other group uses NHP to evaluate MNR effects on placental and F organ structural and functional development in studies not possible in human fetuses. Synergy: All projects study similar mechanisms and use the same baboons to investigate overlapping pathways and provide information on organ similarities and differences. Environment: University of Texas Health Sciences Center and Southwest Foundation for Biomedical Research have collaborated for many years. We have experienced and interactive Cores. Extensive preliminary data support the hypotheses. Investigators: In addition to new investigators, PO1 investigators have collaborated for a total of over 85 years. Summary: We apply for Years 16-20 support. Lay description: We pass more milestones during in utero development than any other time of life. Sub-optimal conditions in utero alter placental function and brain and kidney development. 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 in pregnancy.
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