SPECIFIC AIMS: Our baboon model builds on fetal frontal cortex (FC) findings of delayed development, altered nutrient sensing/cell signaling and hypometaboiism (HM) resulting from IUGR. We study three maternal diets: 1) control (CTR, ad lib), 2) maternal nutrient restriction (MNR, 70% CTR diet) and 3) intervention (INT, MNR plus leucine). Maternal and fetal tissues and blood are obtained at 0.75 and 1.0 gestation (G; 1.0 = 184d) to complement previous studies (0.5, 0.65 and 0.9G). GENERAL HYPOTHESIS: Fetal HM, an indispensable survival strategy in IUGR, enhances survival and differentiataion, but adversely affects development. We show HM, with IUGR, down-regulating large numbers of genes and pathways, e.g., amino acid (AA) transport, mTOR, neurotrophins and promoter methylation. Down-regulation is balanced by up-regulation of key proteins, pathways and genes, e.g. chemokines (CK), reactive oxygen (ROS) and nitrogen (RNS) species. Thus outcomes are not solely due to decreased nutrient availability. Preliminary data show that gene-environment interactions produce HM, decreasing growth, but allowing differentiation for survival. HYPOTHESES: In fetal FC, IUGR: 1) decreases AA transport, 2) down-regulates mTOR nutrient sensing, 3) modifies local and systemic cell signaling and 4) directs ceil function reguiation towards survival/differentiation by mechanisms that decrease mitochondrial function, increase ROS/RNS and induce epigenetic change. Project II Aims: 1) determine if INT ameliorates FC outcomes, 2) determine mechanisms of mTOR and other nutrient sensing systems in FC neurons and glia via tissue obtained in vivo and in cell culture, 3) determine growth and differentiation related mechanisms (e.g. IGF, neurotrophin, and CK signaling) and, 4) determine mechanisms of cell function regulation, mitochondrial, ROS/RNS and epigenetic changes via IHC, biochemistry, ROS/RNS production. Next Gen and cell culture combined with activity detenmined via multiple-well Clark electrode technique. We evaluate target gene epigenetic regulation, changes in one carbon cycle and miRNA expression and compare them to CTR INNOVATION/TRANSLATION: IUGR mechanisms/adaptations cannot be tested in human fetuses. We respond to the NICHD Vision Paper stating the need for comparative studies that focus on nonhuman primates given their similar biology....
IUGR leads to increased post-natal morbidity and mortality. The developmental programming hypothesis cleariy shows that IUGR predisposes to poor lifetime health. Paradigms used, e.g., study of ROS/RNS and essential AA replacement, address the need for therapeutic interventions in IUGR.
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