Sub-optimal fetal (F) organ development is associated with increased neonatal death and long-term morbidity, but mechanisms are poorly understood. We have developed a nonhuman primate (NHP) baboon lUGR model to study effects of three maternal (M) diets: (1) control (CTR, ad lib fed), (2) maternal nutrient reduction (MNR, 70% CTR diet) leading to reduced F nutrition and (3) intervention (INT, MNR plus leucine supplement). We build on years 16-21 in three integrated projects: Project I placenta, II F frontal cortex. III F kidney and three Cores, A. Administrative, B. Animal and C. Genomics, Epigenomics and Proteomics. M and F tissues and blood obtained at 0.75 gestation (G; 140d) and Term (LOG; 180d) complement completed 0.5, 0.65, 0.9 G studies, providing five developmental stage data. General Hypotheses: Moderate decreased nutrition - 1: decreases AA availability, 2: down-regulating cellular nutrient sensing pathways, 3: modifying local and systemic cell signaling and 4: directing cell function towards survival and differentiation at the expense of proliferation. Approach: We use a 30% global MNR baboon model to compare MNR with CTR and INT mechanisms. We combine 1) In vivo approaches - stable isotope infusions; 2) biochemical - cell signaling and gene function, with global (Next Gen, proteomics), candidate genes/proteins and in vitro cell culture. Innovation: We seek innovation by combining a unique NHP lUGR model with state of the art techniques to determine mechanisms underlying development of fetal somatic and cellular phenotype. Synergy: Projects study similar mechanisms in the same baboons. We use our depth of expertise to enable one Project to lead in some areas, informing others with its results e.g. reactive oxygen and nitrative stress data comes from Project II. Project III leads the proteomic and miRNA approaches. Environment: The CPNR and TBRI have collaborated for 26 years. Investigators: We have collaborated together extensively and expanded our team showing continuity, productivity and initiative to change. In summary: We use a unique combination of approaches to evaluate development of NHP placenta and F brain and kidney. This POl addresses National Children's Study goals. We provide detailed plans and letters of interest for sharing tissues. Lay description: We pass more milestones during fetal development than any other time of life. Studies will determine mechanisms by which prenatal conditions predispose to behavioral disorders, renal and cardiovascular disease and many other chronic non-communicable diseases and are designed to aid development of diagnostic and therapeutic management.
We have developed a unique fetal nonhuman primate lUGR model that shows impaired placental function and fetal cerebral and renal development. Gene-environment interactions during fetal development alter organ differentiation and growth with the result that offspring develop a phenotype predisposing to poor adult health including cognitive and renal disease. The findings of our studies, especially the intervention study, will help to determine underlying mechanisms and lead to potential diagnostic and therapeutic approaches.
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