Fetal Baboon Brain Development In Moderate IUGR

具体目标：我们的狒狒模型建立在胎儿额叶皮层（FC）发育延迟的发现基础上， 由IUGR引起的改变的营养感测/细胞信号传导和低代谢（HM）。我们研究三个 母体饮食：1）对照（CTR，随意），2）母体营养限制（MNR，70%CTR饮食）和3） 干预（INT，MNR加亮氨酸）。在0.75和1.0下获得母体和胎儿组织和血液 妊娠（G; 1.0 = 184天），以补充先前的研究（0.5，0.65和0.9 G）。一般假设： 胎儿HM是IUGR不可或缺的生存策略，可提高存活率和分化， 影响发展。我们显示，患有IUGR的HM下调了大量的基因和途径，例如， 氨基酸（AA）转运、mTOR、神经营养因子和启动子甲基化。下调是平衡的， 关键蛋白、途径和基因的上调，例如趋化因子（CK）、活性氧（ROS）和 氮（RNS）物种。因此，结果不仅仅是由于养分供应减少。初步 数据显示，基因-环境相互作用产生HM，降低生长，但允许分化 为了生存假设：在胎儿FC中，IUGR：1）减少AA转运，2）下调mTOR 营养感测，3）改变局部和全身细胞信号传导，以及4）指导细胞功能调节 通过降低线粒体功能，增加ROS/RNS和 诱导表观遗传变化。项目II目的：1）确定INT是否改善FC结局，2）确定 通过体内获得的组织在FC神经元和神经胶质中的mTOR和其他营养感测系统的机制 和在细胞培养物中，3）确定生长和分化相关机制（例如IGF、神经营养因子，和 CK信号）和，4）确定细胞功能调节、线粒体、ROS/RNS和 通过IHC、生物化学、ROS/RNS产生的表观遗传变化。下一代和细胞培养结合 通过多井克拉克电极技术测定活性。我们评估靶基因表观遗传 调节，一碳循环和miRNA表达的变化，并将其与CTR进行比较 创新/翻译：IUGR机制/适应不能在人类胎儿中测试。我们 回应NICHD的愿景文件，指出需要“比较研究，重点是非人类 灵长类动物有着相似的生物学特性". 相关性（参见说明）： IUGR导致产后发病率和死亡率增加。发展性编程假说 清楚地表明，IUGR易导致终生健康状况不佳。使用的范例，例如，ROS/RNS研究 必需的AA替代，解决IUGR治疗干预的需要。

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...". RELEVANCE (See instructions): 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.