Differential effects of phlebotomy-induced anemia on regional brain metabolism

 描述（由申请人提供）：氧和铁是儿童期大脑结构快速发育的关键代谢底物。贫血导致这两种缺陷，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贫血，其中大部分是由于失血造成的。这 包括美国每年超过300，000名早产新生儿，这些新生儿由于在新生儿重症监护室（NICU）中重复采血而变得严重贫血，并且处于神经发育障碍的高风险中。失血有可能使年轻的大脑缺少氧气和铁，在贫血期间发育最快的大脑结构可能受到影响。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，对人类和临床前啮齿动物模型的广泛研究表明，早期生活饮食缺铁性贫血的长期影响，支持早期生活贫血对大脑有害的假设。一种可能有助于缓解贫血并减轻这些变化的干预措施是施用重组人促红细胞生成素（RhEpo），其刺激红细胞产生，从而增加氧气输送。促红细胞生成素也可以作为一种神经保护剂。 使用与贫血早产儿发育和生理相关的失血性贫血小鼠模型，该提案将使用磁共振波谱（MRS）来确定早期生活中贫血对正常认知发育至关重要的四个大脑区域代谢的影响：小脑，纹状体，海马和前额皮质。目的是询问失血性贫血组与非出血对照组相比，在贫血期间快速生长的区域（海马和纹状体）内是否存在代谢的差异性改变。具体而言，该研究的目的是1）确定重要的四个脑区的神经化学谱是否因贫血而发生差异性改变; 2）确定四个重要脑区的神经化学谱是否在贫血恢复后的成年期保持改变，以及是否存在功能性行为缺陷; 3）确定通过RhEpo给药缓解贫血是否使神经化学谱正常化。为了实现这些目标，体内MRS将测量关键代谢物的局部稳态浓度。离体细胞外通量分析将允许评估神经元生物能量学。定量实时PCR将评估突触可塑性基因表达的变化。长期功能结果将通过解剖学驱动的行为测试进行评估，这些测试对每个大脑区域的功能进行索引。 由缺铁和新生儿大脑发育专家Michael Georgieff博士和MRS技术和分析专家Gülin Öz博士对申请人进行培训，将为她未来使用MRS和其他神经成像技术研究早期神经发育的职业生涯做好准备。

 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.