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质(FC)发育迟缓的结果上， IUGR引起的营养感知/细胞信号改变和低代谢症(HM)。我们研究了三个 母亲饮食：1)对照组(CTR，即席)，2)母亲营养限制(MNR，70%CTR饮食)和3) 干预(INT、MNR+亮氨酸)。母体和胎儿组织和血液分别在0.75和1.0摄取 妊娠(G；1.0=184d)，以补充先前的研究(0.5、0.65和0.9g)。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能力，但对其不利 影响发展。我们发现，患有IUGR的HM下调了大量基因和途径的表达，例如， 氨基酸转运、mTOR、神经营养因子和启动子甲基化。下调监管的平衡是通过 上调关键蛋白质、途径和基因，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的减少。初步 数据显示，基因与环境的相互作用会产生HM，减少生长，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 营养感知，3)改变局部和系统细胞信号，4)指导细胞功能调节 通过降低线粒体功能，增加ROS/RNS和 引发表观遗传变化。项目II的目标：1)确定INT是否改善FC结果，2)确定 MTOR和其他营养传感系统通过体内获取的组织在FC神经元和胶质细胞中的机制 在细胞培养中，3)确定与生长和分化相关的机制(例如，IGF、神经营养因子和 CK信号)和，4)确定细胞功能调节的机制，线粒体，ROS/RNS和 通过IHC、生物化学、ROS/RNS产生的表观遗传学变化。下一代与细胞培养相结合 用多井克拉克电极技术测定活性。我们评估目标基因的表观遗传学 调控、一个碳循环的变化和miRNA的表达，并与CTR进行比较 创新/翻译：IUGR机制/适应不能在人类胎儿身上测试。我们 回应NICHD远景文件，指出需要“以非人类为重点的比较研究” 灵长类动物有着相似的生物学特性……“。 相关性(请参阅说明)： 胎儿宫内发育迟缓导致产后发病率和死亡率增加。发展规划假说 清楚地表明，宫内发育迟缓容易导致终生健康状况不佳。使用的范例，例如ROS/RNS研究和 必要的AA替代，满足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.