Gestational Iron Deficiency disrupts neural patterning in the embryo

妊娠期缺铁会破坏胚胎的神经模式

基本信息

批准号：
10286844
负责人：
MARGOT MAYER-PROSCHEL
金额：
$ 37.42万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10286844
关键词：
Affect Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Amyloid Animal Disease Models Animal Model Behavioral Behavioral Assay Birth Brain Cells Cognitive deficits Defect Deficiency Diseases Demyelinations Development Disease Disease Progression Embryo Environmental Risk Factor Equilibrium Exposure to Funding Goals Herpesviridae Human Hyperactivity Impaired cognition Impairment Infection Inflammation Interneurons Iron Latent virus infection phase Lead Learning Life Link Malnutrition Memory Metals Microtubules Modeling Mutation National Institute of Child Health and Human Development Neurites Neuronal Differentiation Neurons Parvalbumins Pathogenicity Pathologic Pathology Play Population Pregnancy Presenile Alzheimer Dementia Proteins Refractory Research Project Grants Role Senile Plaques Severities Severity of illness Signal Transduction Supplementation Synapses Testing Time Virus Diseases Work cellular pathology cognitive development early life exposure early onset familial Alzheimer disease in vivo iron deficiency iron supplementation mature animal mouse model neural patterning neuron loss novel offspring postnatal relating to nervous system tau Proteins

项目摘要

Abstract This supplemental funding request builds on our EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT-sponsored research grant that is focused on the impact of gestational iron deficiency (GID) on brain development. In the course of this work we have discovered that GID alters neuronal cell populations in the embryonic brain which result in an altered balance of excitatory and inhibitory signaling (E/I balance) later in life. This imbalance, which is associated with a decrease in parvalbumin expressing interneurons (PV) is refractory to postnatal iron supplementation suggesting that the changes that occur in the embryo are permanent and might render the brain vulnerable to other insults later in life. Interestingly, recent studies have found that Alzheimer disease is also associated with an impaired E/I balance and mouse models of Alzheimer disease show a significant reduction in the number of PV- expressing cells in the cortex compared with age-matched wild-type counterparts. These observations, together with our recent findings that GID causes region specific dysregulation of metals in the brain (which is also found in AD), raise the interesting hypothesis that gestational iron deficiency renders offspring more susceptible to Alzheimer disease later in life. We will test this novel hypothesis by establishing double-insult models where we expose animal models of familial AD to GID and test whether GID alters the time of onset of pathology and the severity of AD pathology. As a positive control, we will also combine AD mouse models with our newly generated mouse model of early-life exposure to latent human herpes virus 6 infections (HHV6), a secondary insult that has recently been linked to AD and has been suggested to be a pathology modulator.

抽象的这项补充资金要求建立在我们的Eunice Kennedy Shriver国家研究所的基础上儿童健康与人类发展赞助的研究赠款，该赠款的重点是影响妊娠铁缺乏症（GID）关于大脑发育。在这项工作的过程中，我们发现了 GID改变了胚胎大脑中的神经元细胞群，从而改变了兴奋性和抑制信号传导（E/I平衡）以后生命。这种不平衡，与表达中间神经元（PV）的白蛋白减少对产后补充铁的难治性表明胚胎中发生的变化是永久性的，可能会使大脑呈现容易受到以后生活中其他侮辱的攻击。有趣的是，最近的研究发现，阿尔茨海默氏病也与E/I受损有关阿尔茨海默氏病的平衡和小鼠模型显示，PV-的数量显着减少与年龄匹配的野生型相比，在皮质中表达细胞。这些观察，加上我们最近的发现，即GID引起区域特定的大脑金属失调（在AD中也发现），提出一个有趣的假设，即妊娠铁缺乏效果后代更容易患阿尔茨海默氏病。我们将通过建立双侵入模型来检验这个新的假设家族性广告以GID和测试GID是否改变了病理的发作时间和AD的严重程度病理。作为一个阳性对照，我们还将将AD鼠标模型与新生成的鼠标结合在一起潜在人类疱疹病毒6感染（HHV6）的早期生活模型，一种次要侮辱最近与AD相连，并被认为是病理调节剂。