Newborn iron deficiency

新生儿缺铁

• 批准号: 10217214
• 负责人: Michael K. Georgieff
• 金额: $ 37.73万
• 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/10217214
• 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; 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; dietary; 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; neonatal mice; 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.

铁缺乏症（ID）影响约20亿人，尤其是孕妇及其婴儿。 ID对早期的大脑发育有害，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，在未经治疗和治疗的人群中，学习和记忆力障碍持续到成年。在婴儿期铁治疗后，脑部障碍的持久性意味着仅铁治疗就不足以完全康复，或者铁治疗本身可能是有害的。由于教育和工作潜力失去，早期生活的这些长期影响是对社会的真正成本。胎儿/新生儿大脑具有高度代谢，占全身氧气消耗的60％。海马在新生儿大脑中具有最高的区域代谢率之一。铁为电子传输和能源生产所需的酶提供了催化成分。在小鼠中，早期的海马神经元ID降低了神经元能量代谢，包括氧化磷酸化和糖酵解，将线粒体募集减少到成长中的树突/刺的活性部位，从而增加活性氧（ROS），并扭转了动态性氧（ROS），并扭转了树枝状列石和跨型。尽管有铁充实，这些发现仍然持续到成年。发育ID如何导致长期神经元结构缺陷以及是否可以预防或治疗这些细胞机制尚不清楚。我们将测试总体假设，即海马能量代谢的早期重新编程是对胎儿/新生儿ID的潜在适应性反应，长期适应不良，并导致以前ID ID成人的Hippocampus的结构异常。在AIM 1中，我们将利用慢性新生儿海马神经元ID的独特体外模型来测试疗法，该疗法解决开发过程中ID中断的基本能量过程，以防止神经元结构缺陷。为此，我们将从遗传，营养或药理上操纵铁缺乏的新生儿海马神经元培养物中的特定代谢功能。线粒体氧的消耗速率和细胞糖酵解速率，线粒体募集到生长的树突/棘的活性位点，将根据操作的响应进行测量。结果的树突复杂性和脊柱密度/形态将被评估为结果指标。 AIM 2将AIM 1的体外发现转换为体内小鼠模型，以测试用于新生小鼠的疗法，以防止在成年期的线粒体功能，树突结构和神经认知行为中永久异常。我们独特的非动态，海马神经元特异性/负TFR-1小鼠模型为评估翻译效应提供了完美的平台。该提议非常重要，因为它首次定义了早期生命ID引起的神经元能量代谢的特定缺陷如何独立于贫血导致线粒体代谢和神经学畸形的长期异常。它通过机械和经验得出的疗法来防止它们。