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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

基本信息

批准号：
9568365
负责人：
CHRISTOPHER L COE
金额：
$ 55.7万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-22 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9568365
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 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 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 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

项目摘要

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.