Roles of Iron-Dependent PHD and JARID in Early-Life Iron Deficiency-Induced Adult Neural Gene Dysregulation

铁依赖性 PHD 和 JARID 在生命早期缺铁引起的成人神经基因失调中的作用

基本信息

批准号：
10208976
负责人：
PHU V. TRAN
金额：
$ 32.99万
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：
2017-07-01 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10208976
关键词：
ARID Domain Acute Address Adult Affect Anemia Animal Model Architecture Attenuated BDNF gene Behavioral Biology Brain Brain region Brain-Derived Neurotrophic Factor Cell Line Child Childhood Choline Chromatin Chromatin Structure Chronic Clinical Research Cognition Cognitive Data Deferoxamine Dendrites Development Diagnosis Diet Dietary Iron Differentiation and Growth Dioxygenases Dominant-Negative Mutation Down-Regulation Education Emotional Engineering Epigenetic Process FRAP1 gene Family Folic Acid Functional disorder Future Gene Expression Genes Genetic HIF1A gene Health Care Costs Hippocampus (Brain)Histone H3 Human Hydroxylation Impairment Infant Intake Iron Iron Chelating Agents Iron deficiency anemia Knowledge Lead Learning Life Link Long-Term Effects Longevity Lysine Maintenance Mediating Memory Mental Health Metabolism Modeling Modification Molecular Neurologic Neuronal Differentiation Neuronal Dysfunction Neuronal Plasticity Neurons Neurophysiology - biologic function Nuclear Occupations PF4 Gene Pathway interactions Pregnancy Pregnant Women Procollagen-Proline Dioxygenase Proline Protein Family Proteins Publishing Rattus Regulation Risk Role Schizophrenia Signal Transduction Societies Structure Synapses Synaptic plasticity Tail Testing Therapeutic Time Tissues Transgenic Mice Work autism spectrum disorder base catalyst chromatin modification chromatin remodeling cofactor cost critical period design education cost emotional behavior fetal hippocampal pyramidal neuron histone demethylase histone methylation histone modification human capital infancy insight iron deficiency methyl group micronutrient deficiency mouse model neonatal period neurobehavioral neurodevelopment neuron development neuronal growth novel offspring postnatal prenatal prevent promoter public health relevance ranpirnase relating to nervous system restoration synaptogenesis

项目摘要

ABSTRACT Early-life iron deficiency (ID) affects ~20-30% of all pregnant women and their offspring worldwide and causes long-term impairments in cognition and socio-emotional behaviors in adulthood despite iron therapy after the diagnosis of ID in infancy. These persistent abnormalities constitute a significant cost to society in terms of loss of education, job potential, and mental health. The underlying pathobiology for the persistent behavioral abnormalities has been ascribed solely to abnormal neural development and function (e.g., metabolism, dendritogenesis, and synaptogenesis) during critical periods in early life that are carried forward into adulthood (function follows form hypothesis). However, major gaps in knowledge remain, one of which pertains to the iron-dependent cellular mechanisms, by which early-life ID induces the dysregulation of genes critical for neuronal function in adulthood. Such knowledge is critical to advance the field in terms of therapeutic strategies to prevent the long-term negative effects of early-life ID on the developing brain. The present proposal investigates how cellular pathways driven by iron-containing dioxygenases alter long-term neuronal expression of major synaptic differentiation and plasticity genes, including brain-derived neurotrophic factor (BDNF). We leverage the necessity of iron for the catalytic activity of two well-known families of dioxygenases, prolyl hydroxylases (PHDs) and JmjC ARID-domain containing histone demethylases (JARIDs), to analyze the functional effect of early-life ID on these proteins in neural tissues. Our novel conceptualization is that the two pathways are linked through PHD regulation of HIF1α, which in turns targets JARIDs. Based on our recent published findings and new preliminary data, we will show that early-life ID alters the function of both PHD and JARID, leading to stable epigenetic modifications and consequent gene dysregulation in adulthood. We will test this novel hypothesis using our unique chronic iron-deficient primary cultured hippocampal-pyramidal neuron model and our dominant-negative (DN) TfR1 transgenic mouse model that was engineered to induce ID specifically in the developing neurons in a time-dependent manner without systemic anemia or global brain ID. We will further demonstrate the translational value of this concept using the dietary ID anemia rat model that closely resembles the human condition. The proposed work will have a major impact on the field by addressing two important gaps in knowledge: (1) whether PHDs and JARIDs are key iron-containing factors directly responsible for the changes in chromatin structures, resulting in the persistent dysregulation of genes critical for learning and memory; and (2) whether timely iron restoration can attenuate these modifications. Closing these gaps is crucial in designing strategies, including maintenance of iron sufficiency during pregnancy and devising potential therapies that restore the epigenetic landscape (e.g., choline), to lessen the life-long burden of millions of children with early-life ID.

抽象的全球约有 20-30% 的孕妇及其后代患有生命早期缺铁 (ID) 尽管进行了铁剂治疗，但仍会导致成年后认知和社会情感行为的长期损害在婴儿期诊断出智力障碍后，这些持续的异常现象给社会造成了巨大的损失。教育、工作潜力和心理健康方面的损失。行为异常仅归因于神经发育和功能异常（例如，新陈代谢、树突发生和突触发生）在生命早期的关键时期被延续到成年期（功能遵循形式假设）然而，知识方面仍然存在重大差距，其中之一。与铁依赖性细胞机制有关，生命早期 ID 会通过该机制诱导基因失调这些知识对于成年后的神经功能至关重要。防止生命早期智力缺陷对发育中的大脑产生长期负面影响的策略。本提案研究了含铁双加氧酶驱动的细胞途径如何改变主要突触分化和可塑性基因的长期神经元表达，包括脑源性基因我们利用铁对两种众所周知的催化活性的必要性。双加氧酶家族、脯氨酰羟化酶 (PHD) 和含有组蛋白脱甲基酶的 JmjC ARID 结构域（JARID），分析早期 ID 对神经组织中这些蛋白质的功能影响。概念化是，这两条途径通过 PHD 对 HIF1α 的调节联系起来，而 HIF1α 反过来又靶向根据我们最近发表的研究结果和新的初步数据，我们将证明生命早期的 ID 会发生变化。 PHD 和 JARID 的功能，导致稳定的表观遗传修饰和后续基因我们将利用我们独特的慢性缺铁原发性疾病来检验这一新假设。培养的海马锥体神经元模型和我们的显性失活（DN）TfR1转基因小鼠模型它被设计为以时间依赖的方式在发育中的神经元中特异性诱导 ID，而无需系统性贫血或全球大脑 ID 我们将进一步证明这个概念的转化价值。饮食性贫血大鼠模型与人类状况非常相似。拟议的工作将通过解决两个重要的知识差距对该领域产生重大影响：（1）PHD和JARID是否是直接导致染色质变化的关键含铁因子结构，导致对学习和记忆至关重要的基因持续失调；以及（2）是否及时补充铁可以减弱这些变化，这对于设计策略至关重要。包括在怀孕期间维持充足的铁质以及设计恢复铁质的潜在疗法表观遗传景观（例如胆碱），以减轻数百万早年智力障碍儿童的终生负担。