Detection and Correction of Iron Deficiency Induced Abnormal Brain Metabolism

项目摘要/摘要 长期的认知和行为缺陷是3岁前缺铁(ID)的后遗症 孩子们。啮齿动物早期智力缺陷与脑功能障碍之间的因果关系已被确立 模型，但由于缺乏脑铁状态和功能的外周生物标志物，在人类中不太清楚。 使用一种非人类灵长类动物模型，该模型密切模拟人类铁的生物学、大脑发育和新陈代谢， 我们建议发现新的生物标记物来指示ID和ID贫血前阶段的脑功能障碍 评价早期铁剂治疗对减轻缺铁性脑功能障碍的疗效。我们将陆续 从出生到12个月的测量，常规的血液学和铁相关指标，以及新的蛋白质组学- 和基于代谢组学的生物标记物在智障婴儿的血(血清)和鞘内(CSF)间隔中的作用 铁充足的对照组婴儿，以神经解剖学(MRI)和功能(行为)评估结束。 AIM 1将确定如何最好地利用血清蛋白质组学和代谢组学来检测即将到来的ID- 通过描述哪些分析物以及在ID过程中的时间，血清蛋白质组和 代谢组学准确地反映了大脑的代谢、结构和功能损伤。我们预测 反映不同铁调节途径的特定蛋白质和代谢物的变化将在 在贫血前期的血清中，并提供即将发生脑功能障碍的生物标志物。目标2将量化和 常规血液学和血清铁参数检测脑功能障碍的敏感性模型 通过连续监测这些参数与脑功能障碍的代谢组和蛋白质组指标相关 在同时获得的脑脊液中。我们预测，大脑ID和功能障碍在出现之前就会很明显 贫血，表明临床上使用的血液学参数是不敏感的生物标志物 脑铁和代谢状态。目标3将检验这一假设，即在贫血之前进行铁治疗是必要的 为了减轻ID.ID的不良神经影响，ID.ID婴儿将随机接受铁质治疗 贫血前期或贫血后发展为缺铁性贫血。两种修复方法的疗效比较 将测定血液学指标和脑铁状态、代谢、结构和功能。我们预测 这两种治疗方法都将使血液学指标正常化，但只有铁治疗始于贫血前期。 阶段将全面恢复脑铁状态、新陈代谢、结构和功能。这个项目意义重大，因为 它侧重于早期筛查和干预对改善儿童神经发育的好处 它具有创新性，因为它将使用新的蛋白质组和代谢组学分析来 同时探测灵长类动物模型中的血液和鞘内隔室，该模型独特地模仿了铁 和人类婴儿的新陈代谢需求。功能性生物标志物的发现将实现我们的终极目标 优化早期脑ID高危儿童的筛查和治疗策略的翻译目标。

PROJECT SUMMARY/ABSTRACT Long-term cognitive and behavioral deficits are the sequelae of iron deficiency (ID) prior to 3 years of age in children. A causal relationship between early-life ID and brain dysfunction has been established in rodent models, but not as clearly in humans due to a lack of peripheral biomarkers of brain iron status and function. Using a nonhuman primate model that closely mimics human iron biology, brain development and metabolism, we propose to discover novel biomarkers that index brain dysfunction in the pre-anemic stage of ID and evaluate the efficacy of early iron treatment for mitigating ID-induced brain dysfunction. We will serially measure from birth until 12 months, conventional hematological and iron-related indices, and novel proteomic- and metabolomic-based biomarkers in the blood (serum) and intrathecal (CSF) compartments of ID infants and iron sufficient control infants, concluding with neuroanatomical (MRI) and functional (behavior) assessments. Aim 1 will determine how best to employ serum proteomics and metabolomics to detect impending ID- induced brain dysfunction by delineating which analytes and when in the course of ID, the serum proteome and metabolome accurately reflect the brain metabolic, structural and functional impairments. We predict that specific protein and metabolite changes reflecting distinct iron-regulated pathways will be detected in the serum in the pre-anemic period and provide biomarkers of impending brain dysfunction. Aim 2 will quantify and model the sensitivity of conventional hematological and serum iron parameters for detecting brain dysfunction by serially monitoring these parameters relative to the metabolomic and proteomic indices of brain dysfunction in concurrently obtained CSF. We predict that brain ID and dysfunction will be evident prior to the appearance of anemia, indicating that hematological parameters used in clinical practice are insensitive as biomarkers of brain iron and metabolic status. Aim 3 will test the hypothesis that iron treatment prior to anemia is essential to mitigate the adverse neurological effects of ID. ID infants will be randomized to iron treatment either in the pre-anemic stage of ID or after the development of anemia. The efficacy of the two therapies for restoring hematological indices and brain iron status, metabolism, structure and function will be determined. We predict that both treatments will normalize hematological indices, but only iron treatment begun in the pre-anemic stage will fully restore brain iron status, metabolism, structure and function. This project is significant, because it focuses on the benefits of early screening and interventions for improving the neurodevelopment of children at risk for early-life ID. It is innovative because it will employ novel proteomic and metabolomic analyses to simultaneously probe the blood and intrathecal compartments in a primate model that uniquely mimics the iron and metabolic demands of the human infant. The discovery of functional biomarkers will achieve our ultimate translational goal of optimizing screening and treatment strategies in children at risk for early-life brain ID.