Differential effects of phlebotomy-induced anemia on regional brain metabolism

放血引起的贫血对区域脑代谢的不同影响

• 批准号: 9095853
• 负责人: Diana J. Wallin
• 金额: $ 2.97万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-15 至 2017-12-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9095853
• 关键词: Acute; Adult; Affect; Anemia; Animals; Area; Attenuated; Behavioral; Bioenergetics; Blood; Blood specimen; Brain; Brain region; Cell Respiration; Cerebellum; Cerebrum; Child; Childhood; Clinical Research; Cognitive deficits; Consumption; Corpus striatum structure; Development; Dietary Iron; Dose; Early treatment; Energy Metabolism; Erythrocytes; Erythropoietin; Future; Gene Expression; Glucose; Glutamates; Goals; Growth; Health; Hemorrhage; Hippocampus (Brain); Homeostasis; Human; Hypoxia; Impaired cognition; Intervention; Iron; Iron deficiency anemia; Lead; Learning; Life; Long-Term Effects; Magnetic Resonance Spectroscopy; Measures; Memory; Metabolic; Metabolism; Modeling; Mus; Neonatal; Neonatal Intensive Care Units; Neurodevelopmental Impairment; Neurons; Neuroprotective Agents; Neurosciences; Outcome; Oxygen; Performance; Physicians; Prefrontal Cortex; Premature Infant; Prevention; Production; Recovery; Research; Risk; Rodent Model; Structure; Synaptic plasticity; Techniques; Testing; Time; Training; Venous blood sampling; behavior test; brain metabolism; career; cognitive development; extracellular; fetal; functional outcomes; high risk; in vivo; indexing; insight; iron deficiency; mouse model; myelination; neonatal brain; neurochemistry; neurodevelopment; neuroimaging; neurotransmission; oxygen debt; phosphoethanolamine; postnatal; pre-clinical; prevent; rapid growth; recombinant human erythropoietin; response

 DESCRIPTION (provided by applicant): Oxygen and iron are critical metabolic substrates for rapidly developing brain structures in childhood. Anemia, which causes a deficit of both, is a common pediatric problem that is associated with long- term neurodevelopmental impairment. Estimates indicate that half of the world's children are anemic, much of it due to blood loss. This includes over 300,000 preterm neonates per year in the US who become profoundly anemic due to repeated blood sampling in the neonatal intensive care unit (NICU) and are at high risk for neurodevelopmental impairment. Blood loss risks shortchanging the young brain of oxygen and iron, and the brain structures that are most rapidly developing during the period of anemia are likely to be affected. Few if any clinical studies have directly assessed the short and long-term neurodevelopmental effects of blood-loss anemia in preterm infants. However, extensive studies in humans and preclinical rodent models have shown the long-term effects of early life dietary iron deficiency anemia, supporting the hypothesis that early life anemia is detrimental to the brain. One intervention which may help to alleviate the anemia and lessen these changes is administration of recombinant human erythropoietin (RhEpo) which stimulates red blood cell production, thereby increasing oxygen delivery. Erythropoietin may also act as a neuroprotectant. Using a mouse model of blood loss anemia that is both developmentally and physiologically relevant to anemic preterm infants, this proposal will use magnetic resonance spectroscopy (MRS) to determine the effect of anemia during early-life on the metabolism of four brain regions critical to normal cognitive development: cerebellum, striatum, hippocampus and prefrontal cortex. The objective is to ask whether there are differential alterations to metabolism in the blood loss anemia group as compared to non-bled controls within regions that are rapidly growing during the period of anemia (hippocampus and striatum). Specifically, the study aims are to 1) determine whether the neurochemical profiles of important four brain regions are altered differentially by anemia; 2) determine whether the neurochemical profiles of four important brain regions remain altered in adulthood after recovery from anemia and whether there are functional behavioral deficits; and 3) determine whether alleviation of anemia through RhEpo administration normalizes the neurochemical profiles. To accomplish these aims, in vivo MRS will measure the regional steady-state concentrations of critical metabolites. Ex vivo extracellular flux analysis will allow assessment of neuronal bioenergetics. Quantitative real-time PCR will assess synaptic plasticity gene expression changes. Long-term functional outcomes will be assessed via anatomically driven behavioral tests that index the functionality of each brain region. Training of the applicant by Dr. Michael Georgieff, an expert in iron deficiency and neonatal brain development, and Dr. Gülin Öz, an expert in MRS techniques and analysis, will prepare her well for a future career researching early neurodevelopment using MRS and other neuroimaging techniques.

 描述(申请人提供)：氧气和铁是儿童时期大脑结构快速发育的关键代谢底物。贫血导致两者都缺乏，是一种常见的儿科问题，与长期的神经发育障碍有关。据估计，世界上有一半的儿童患有贫血，其中很大一部分是由于失血。这 包括美国每年超过300,000名早产儿，他们因在新生儿重症监护病房(NICU)反复采血而严重贫血，并面临神经发育障碍的高风险。失血可能会使年轻的大脑缺乏氧气和铁，而在贫血期间发育最快的大脑结构可能会受到影响。很少有临床研究直接评估失血性贫血对早产儿神经发育的短期和长期影响。然而，在人类和临床前啮齿动物模型中的广泛研究表明，早期饮食缺铁性贫血的长期影响，支持了早期生活性贫血对大脑有害的假说。一种可能有助于缓解贫血和减轻这些变化的干预措施是注射重组人促红细胞生成素(RhEPO)，它刺激红细胞生成，从而增加氧气输送。促红细胞生成素也可以起到神经保护剂的作用。使用与早产儿贫血在发育和生理上都相关的失血性贫血小鼠模型，这项提议将使用磁共振波谱(MRS)来确定早期贫血对四个对正常认知发育至关重要的大脑区域：小脑、纹状体、海马体和前额叶皮质代谢的影响。目的是询问失血性贫血组与非失血对照组相比，在贫血期间迅速增长的区域(海马体和纹状体)内，是否存在代谢的不同变化。具体地说，这项研究的目的是：1)确定重要的四个大脑区域的神经化学图谱是否因贫血而发生不同的变化；2)确定四个重要大脑区域的神经化学图谱在成年后是否从贫血中恢复，以及是否存在功能行为缺陷；以及3)确定给予重组人促红细胞生成素治疗贫血是否使神经化学图谱正常化。为了实现这些目标，体内MRS将测量关键代谢物的区域稳态浓度。体外细胞外通量分析将允许对神经元生物能量学进行评估。实时定量聚合酶链式反应将评估突触可塑性基因表达的变化。长期的功能结果将通过解剖学驱动的行为测试进行评估，这些测试索引每个大脑区域的功能。由缺铁和新生儿脑发育专家Michael Georgief博士和MRS技术和分析专家GülinÖz博士对申请者进行的培训将使她为未来使用MRS和其他神经成像技术研究早期神经发育做好准备。