Newborn iron deficiency

新生儿缺铁

• 批准号: 9762150
• 负责人: Michael K. Georgieff
• 金额: $ 38.5万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-13 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9762150
• 关键词: Accounting; Active Sites; Acute; Address; Adult; Affect; Anemia; Anxiety; Area; Behavior; Behavioral; Biochemical; Biogenesis; Brain; Cell Culture Techniques; Cells; Child; Chronic; Citric Acid Cycle; Clinical; Clinical Trials; Data; Dendrites; Dendritic Spines; Developed Countries; Developing Countries; Development; Diet; Dominant-Negative Mutation; Education; Electron Transport; Electrophysiology (science); Energy Metabolism; Enzymes; Erythrocytes; Event; Exhibits; Functional disorder; Generations; Genetic; Glycolysis; Goals; Health; Hippocampus (Brain); Human; Impairment; In Vitro; Incidence; Infant; Intervention; Iron; Lead; Learning; Life; Life Style; Liver; Long-Term Effects; Longevity; Malaria; Malnutrition; Measures; Memory; Memory impairment; Mental Depression; Mental disorders; Metabolic; Metabolic dysfunction; Metabolism; Mitochondria; Molecular; Morphology; Mus; Neonatal; Nervous System Physiology; Neurocognitive; Neurocognitive Deficit; Neurologic Deficit; Neurons; Newborn Infant; Nutrient; Nutritional; Occupations; Organ; Outcome Measure; Oxidative Phosphorylation; Oxygen Consumption; Pancreas; Pharmacology; Population; Pregnancy; Pregnant Women; Preventive therapy; Process; Production; Public Health; Publishing; Reactive Oxygen Species; Recommendation; Recovery; Research; Risk; Role; Skeletal Muscle; Societies; Structural defect; Structure; Structure of beta Cell of islet; Synapses; Testing; Time; Translating; Vertebral column; autism spectrum disorder; cell motility; cognitive performance; cost; critical period; density; early childhood; electron energy; experimental study; fetal; improved; in vitro Model; in vivo; infancy; insight; iron deficiency; memory encoding; metabolic rate; mitochondrial dysfunction; mitochondrial metabolism; mouse model; neonatal brain; neonate; neuronal metabolism; nutrition; postnatal; prevent; recruit; response; synaptogenesis; therapy design

Iron deficiency (ID) affects an estimated 2 billion people, especially pregnant women and their infants. ID is harmful to early-life brain development and causes learning and memory deficits in children. More troubling from a public health perspective is that the learning and memory impairments persist into adulthood in both untreated as well as treated populations. Persistence of brain impairment following iron treatment in infancy implies that iron therapy alone is not sufficient for full recovery or that iron therapy itself may be harmful. These long-term effects of early-life ID are the real cost to society because of lost education and job potential. The fetal/neonatal brain is highly metabolic, accounting for 60% of total body oxygen consumption. The hippocampus has one of the highest regional metabolic rates in the neonatal brain. Iron provides the catalytic component for enzymes required for electron transport and energy production. In mice, early-life hippocampal neuronal ID reduces neuronal energy metabolism including oxidative phosphorylation and glycolysis, slows mitochondrial recruitment to active sites of growing dendrites/spines, increases reactive oxygen species (ROS) and truncates dendrite and synapse development. These findings persist into adulthood despite iron repletion. The cellular mechanisms of how developmental ID causes long-term neuronal structural deficits and whether these can be prevented or treated are unclear. We will test the overall hypothesis that early-life reprogramming of hippocampal energy metabolism, which is a potentially adaptive response to fetal/neonatal ID, becomes maladaptive in the long-term and results in structural abnormalities in the formerly ID adult hippocampus. In Aim 1, we will utilize a unique in vitro model of chronic neonatal hippocampal neuronal ID to test therapies that address fundamental energy processes disrupted by ID during development in order to prevent neuronal structural deficits. To do this, we will genetically, nutritionally or pharmacologically manipulate specific metabolic functions in iron-sufficient and -deficient neonatal hippocampal neuron cultures. Mitochondrial oxygen consumption rate and cellular glycolytic rate, mitochondrial recruitment to active sites of growing dendrites/spines and ROS will be measured in response to the manipulations. Resultant dendrite complexity and spine density/morphology will be assessed as outcome measures. Aim 2 translates Aim 1's in vitro findings to an in vivo mouse model to test which therapies delivered to the neonatal mouse prevent permanent abnormalities in mitochondrial function, dendrite structure and neurocognitive behavior in adulthood. Our unique non-anemic, hippocampal neuron-specific dominant/negative TfR-1 mouse model provides the perfect platform to assess the translational effects. This proposal is highly significant because it defines for the first time how the specific deficits in neuronal energy metabolism induced by early-life ID independent of anemia lead to long-term abnormalities in mitochondrial metabolism and neurological deficits. It tests mechanistically and empirically derived therapies to prevent them.

据估计，缺铁 (ID) 影响着 20 亿人，尤其是孕妇及其婴儿。智力障碍对早期大脑发育有害，并导致儿童学习和记忆缺陷。从公共卫生的角度来看，更令人不安的是，无论是未经治疗的人群还是接受治疗的人群，学习和记忆障碍都会持续到成年。婴儿期铁剂治疗后持续出现脑损伤意味着仅铁剂疗法不足以完全康复，或者铁剂疗法本身可能有害。早年智力缺陷的长期影响是社会因失去教育和工作潜力而付出的真正代价。胎儿/新生儿大脑具有高度代谢能力，占全身耗氧量的60%。海马体是新生儿大脑中代谢率最高的区域之一。铁为电子传输和能量产生所需的酶提供催化成分。在小鼠中，生命早期的海马神经元 ID 会降低神经元能量代谢，包括氧化磷酸化和糖酵解，减缓线粒体向生长树突/棘的活性位点的募集，增加活性氧 (ROS) 并截断树突和突触发育。尽管补充了铁，这些发现仍然持续到成年。发育性智力障碍如何导致长期神经元结构缺陷的细胞机制以及是否可以预防或治疗这些缺陷的细胞机制尚不清楚。我们将检验总体假设，即生命早期海马能量代谢的重新编程（这是对胎儿/新生儿 ID 的潜在适应性反应），从长远来看会变得适应不良，并导致以前 ID 成人海马的结构异常。在目标 1 中，我们将利用一种独特的慢性新生儿海马神经元 ID 体外模型来测试治疗方法，以解决发育过程中 ID 扰乱的基本能量过程，以防止神经元结构缺陷。为此，我们将从遗传、营养或药理学角度操纵铁充足和铁缺乏的新生儿海马神经元培养物中的特定代谢功能。线粒体耗氧率和细胞糖酵解率、线粒体募集到生长树突/棘的活性位点和活性氧将根据操作进行测量。由此产生的树突复杂性和脊柱密度/形态将作为结果测量进行评估。目标 2 将目标 1 的体外研究结果转化为体内小鼠模型，以测试给予新生小鼠的哪些疗法可以预防成年小鼠线粒体功能、树突结构和神经认知行为的永久性异常。我们独特的非贫血、海马神经元特异性显性/阴性 TfR-1 小鼠模型提供了评估转化效应的完美平台。这项提议非常重要，因为它首次定义了生命早期 ID 引起的神经元能量代谢的特定缺陷（与贫血无关）如何导致线粒体代谢和神经缺陷的长期异常。它测试机械和经验派生的疗法来预防它们。