Detection and Correction of Iron Deficiency Induced Abnormal Brain Metabolism

缺铁引起的脑代谢异常的检测和纠正

• 批准号: 10190978
• 负责人: CHRISTOPHER L COE
• 金额: $ 53.5万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-22 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10190978
• 关键词: 3 year old; Aftercare; Anemia; Animal Model; Appearance; Behavior assessment; Behavioral; Biological Markers; Biology; Birth; Blood; Brain; Cerebrospinal Fluid; Child; Childhood; Cognitive; Corpus striatum structure; Data; Detection; Development; Developmental Disabilities; Diagnosis; Diet; Early Diagnosis; Early Intervention; Early treatment; Energy Metabolism; Equilibrium; Experimental Designs; Ferritin; Functional disorder; Goals; Health; Hematology; Heme; Human; Impairment; Infant; Iron; Iron deficiency anemia; Life; Longevity; Macaca mulatta; Magnetic Resonance Imaging; Measures; Metabolic; Metabolism; Methods; Modeling; Monitor; Monkeys; National Institute of Child Health and Human Development; Neurologic Deficit; Neurologic Effect; Outcome Measure; Pathway interactions; Peripheral; Population; Pregnant Women; Prevalence; Primates; Program Development; Proteins; Proteome; Proteomics; Protoporphyrins; Randomized; Recommendation; Research; Resolution; Rhesus; Risk; Rodent Model; Sampling; Serum; Structure; Supplementation; Testing; Time; Tissues; Transferrin; United States National Institutes of Health; Zinc; base; behavior test; blood-based biomarker; brain abnormalities; brain dysfunction; brain metabolism; clinical practice; cohort; dietary supplements; early screening; efficacy evaluation; functional disability; hepcidin; high risk population; improved; indexing; infant animal; innovation; iron deficiency; iron supplementation; metabolome; metabolomics; micronutrient deficiency; neurobehavioral; neurodevelopment; neuroimaging; neuroprotection; nonhuman primate; novel; novel marker; nutrition; prevent; protein metabolite; public health relevance; repaired; screening; societal costs; standard care; tandem mass spectrometry; treatment strategy

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.

项目摘要/摘要 长期认知和行为缺陷是3岁之前的铁缺乏症（ID）的后遗症 孩子们。啮齿动物中已经建立了早期ID与脑功能障碍之间的因果关系 模型，但由于缺乏脑铁状态和功能的外周生物标志物而在人类中并不清楚。 使用非人类的灵长类动物模型，该模型紧密模仿人铁生物学，脑发育和代谢， 我们建议发现在ID和ID前动手阶段和 评估早期铁处理能够减轻ID诱导的脑功能障碍的功效。我们将连续 从出生到12个月的测量，传统的血液学和铁相关指数，以及新颖的蛋白质组学 - ID婴儿的血液（血清）和鞘内（CSF）中的基于代谢组的生物标志物和 铁足够的控制婴儿，以神经解剖学（MRI）和功能（行为）评估结束。 AIM 1将确定如何最好地使用血清蛋白质组学和代谢组学来检测即将来临的ID- 通过描述哪些分析物以及在ID过程中，血清蛋白质组和 代谢组准确地反映了大脑代谢，结构和功能障碍。我们预测 特定的蛋白质和代谢物变化将在 血清在动物前时期，并提供了即将发生的脑功能障碍的生物标志物。 AIM 2将量化并 模拟传统血液学和血清铁参数的灵敏度，以检测脑功能障碍 通过序列监测这些参数相对于脑功能障碍的代谢组和蛋白质组学指数 在同时获得的CSF中。我们预测，在出现之前，大脑ID和功能障碍将显而易见 贫血，表明在临床实践中使用的血液学参数不敏感作为生物标志物 脑铁和代谢状态。 AIM 3将检验以下假设：贫血之前的铁治疗是必不可少的 减轻ID的不良神经效应。 ID婴儿将在 ID前阶段或贫血发生后。两种疗法的恢复功效 血液学指数和脑铁的状态，代谢，结构和功能将被确定。我们预测 两种疗法都将使血液学指数归一化，但仅在贫血前开始 阶段将完全恢复脑铁的状态，代谢，结构和功能。这个项目很重要，因为 它着重于早期筛查和改善儿童神经发育的益处 有生命ID的风险。它具有创新性，因为它将采用新颖的蛋白质组学和代谢组分分析 同时在灵长类动物模型中探测血液和鞘内室，该模型独特地模仿铁 和人类婴儿的代谢需求。功能生物标志物的发现将达到我们的最终 在有生命早期大脑ID风险的儿童中优化筛查和治疗策略的翻译目标。

项目成果

Maternal determinants of gestation length in the rhesus monkey.

• DOI: 10.31300/tdb.14.2021.63-72
• 发表时间: 2021
• 期刊: Trends in developmental biology
• 作者: Coe, Christopher L;Lubach, Gabriele R
• 通讯作者: Lubach, Gabriele R

Gut Microbial and Metabolic Profiling Reveal the Lingering Effects of Infantile Iron Deficiency Unless Treated with Iron.

• DOI: 10.1002/mnfr.202001018
• 发表时间: 2021-04
• 期刊: Molecular nutrition & food research
• 影响因子: 5.2
• 作者: Mayneris-Perxachs J;Amaral W;Lubach GR;Lyte M;Phillips GJ;Posma JM;Coe CL;Swann JR
• 通讯作者: Swann JR

The importance of iron deficiency in pregnancy on fetal, neonatal, and infant neurodevelopmental outcomes.

• DOI: 10.1002/ijgo.14951
• 发表时间: 2023-08
• 期刊: International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics
• 作者: Michael K. Georgieff

Infantile Iron Deficiency Affects Brain Development in Monkeys Even After Treatment of Anemia.

• DOI: 10.3389/fnhum.2021.624107
• 发表时间: 2021
• 期刊: Frontiers in human neuroscience
• 影响因子: 2.9
• 作者: Vlasova RM;Wang Q;Willette A;Styner MA;Lubach GR;Kling PJ;Georgieff MK;Rao RB;Coe CL
• 通讯作者: Coe CL

Ironing Out the Details of Maternal-Fetal Iron Trafficking: New Tools in the Toolbox.

消除母胎铁贩运的细节：工具箱中的新工具。

• DOI: 10.1093/jn/nxab247
• 发表时间: 2021
• 期刊: The Journal of nutrition
• 作者: Kling,PamelaJ