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，约有20亿人患有缺铁症，尤其是孕妇及其婴儿。ID对早期大脑发育有害，并导致儿童学习和记忆障碍。从公共卫生的角度来看，更令人担忧的是，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。婴儿接受铁剂治疗后脑损伤持续存在，这意味着铁剂治疗本身并不足以完全康复，或者铁剂疗法本身可能是有害的。早期智障的这些长期影响是社会的真正代价，因为失去了教育和就业潜力。胎儿/新生儿的大脑是高度新陈代谢的，占全身总耗氧量的60%。海马体是新生儿大脑中区域代谢率最高的区域之一。铁为电子传递和能量生产所需的酶提供催化成分。在小鼠中，早期的海马神经元ID降低了神经元的能量代谢，包括氧化磷酸化和糖酵解，减缓了线粒体招募到生长中的树突/棘突的活性部位，增加了活性氧物种(ROS)，并截断了树突和突触的发育。尽管铁缺乏，但这些发现一直持续到成年。发育性ID如何导致长期的神经元结构缺陷，以及这些缺陷是否可以预防或治疗，其细胞机制尚不清楚。我们将测试总体假设，即早期生命重新编程的海马体能量代谢，这是对胎儿/新生儿ID的潜在适应性反应，从长远来看，变得不适应，并导致以前的ID成人海马区的结构异常。在目标1中，我们将利用一个独特的慢性新生海马神经元ID的体外模型来测试治疗方法，这些治疗方法解决了ID在发育过程中扰乱基本能量过程的问题，以防止神经元结构缺陷。为此，我们将在铁充足和铁缺乏的新生海马神经元培养中，从遗传、营养或药物方面操纵特定的代谢功能。作为对操作的响应，将测量线粒体耗氧率和细胞糖酵解率，线粒体对生长的树突/棘和ROS活性部位的招募。由此产生的树突复杂性和棘突密度/形态将作为结果指标进行评估。目的2将Aim 1‘S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治疗方法可以预防成年后线粒体功能、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小鼠模型为评估翻译效果提供了完美的平台。这一建议具有非常重要的意义，因为它首次定义了由非贫血的早期生命ID诱导的神经元能量代谢的特异性缺陷是如何导致线粒体代谢的长期异常和神经缺陷的。它测试了机械和经验派生的疗法来预防它们。