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.
|Vega, C C; Reyes-Castro, L A; Bautista, C J et al. (2015) Exercise in obese female rats has beneficial effects on maternal and male and female offspring metabolism. Int J Obes (Lond) 39:712-9|
|Kavitha, Jovita V; Rosario, Fredrick J; Nijland, Mark J et al. (2014) Down-regulation of placental mTOR, insulin/IGF-I signaling, and nutrient transporters in response to maternal nutrient restriction in the baboon. FASEB J 28:1294-305|
|Abu Shehab, Majida; Damerill, Ian; Shen, Tong et al. (2014) Liver mTOR controls IGF-I bioavailability by regulation of protein kinase CK2 and IGFBP-1 phosphorylation in fetal growth restriction. Endocrinology 155:1327-39|
|Tchoukalova, Y D; Krishnapuram, R; White, U A et al. (2014) Fetal baboon sex-specific outcomes in adipocyte differentiation at 0.9 gestation in response to moderate maternal nutrient reduction. Int J Obes (Lond) 38:224-30|
|Ye, Wenrui; Xie, Lynn; Li, Cun et al. (2014) Impaired development of fetal serotonergic neurons in intrauterine growth restricted baboons. J Med Primatol 43:284-287|
|Regnault, Timothy R H; Nijland, Mark J; Budge, Helen et al. (2013) Basic experimental and clinical advances in the mechanisms underlying abnormal pregnancy outcomes. J Pregnancy 2013:327638|
|Brocato, B; Zoerner, A A; Janjetovic, Z et al. (2013) Endocannabinoid crosstalk between placenta and maternal fat in a baboon model (Papio spp.) of obesity. Placenta 34:983-9|
|Li, Cun; Ramahi, Emma; Nijland, Mark J et al. (2013) Up-regulation of the fetal baboon hypothalamo-pituitary-adrenal axis in intrauterine growth restriction: coincidence with hypothalamic glucocorticoid receptor insensitivity and leptin receptor down-regulation. Endocrinology 154:2365-73|
|Maloyan, Alina; Muralimanoharan, Sribalasubashini; Huffman, Steven et al. (2013) Identification and comparative analyses of myocardial miRNAs involved in the fetal response to maternal obesity. Physiol Genomics 45:889-900|
|Li, Cun; McDonald, Thomas J; Wu, Guoyao et al. (2013) Intrauterine growth restriction alters term fetal baboon hypothalamic appetitive peptide balance. J Endocrinol 217:275-82|
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