Iron Acquisition Mechanisms in Oligodendrocytes

少突胶质细胞的铁获取机制

基本信息

批准号：
7730664
负责人：
JAMES Robert CONNOR
金额：
$ 34.34万
依托单位：
PENNSYLVANIA STATE UNIV HERSHEY MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7730664
关键词：
2&apos ,3&apos -Cyclic-Nucleotide Phosphodiesterases Adult Affect Antigen-Presenting Cells Appearance Autoradiography Binding Binding Proteins Biochemical Biological Assay Brain Bromodeoxyuridine Buffers CDK2 gene CDK4 gene Cell Count Cell Culture Techniques Cell Cycle Cell Cycle Arrest Cell Cycle Proteins Cell Death Cell Nucleus Cell Survival Cells Ceruloplasmin Characteristics Cognitive Control Groups Culture Media Cyclin E Cyclins DNA biosynthesis Data Demyelinating Diseases Development Diet Disease Enzymes Exclusion Exposure to Family Ferritin Future Genotype H ferritin Immune system Immunoglobulins In Situ Nick-End Labeling In Vitro Incubated Infant Intervention Iron Knockout Mice Knowledge L-ferritin Label Laboratories Life Ligands Luxol Fast Blue MBS Mediating Methods Modeling Molecular Profiling Mucins Multiple Sclerosis Mus Mutate Myelin Myelin Basic Proteins Nervous System Physiology Neurologic Newborn Infant Nutrient Nutrition Disorders Oligodendroglia Outcome Outcome Measure Outcome Study Pattern Phenotype Proteins Quality Control Quantitative Autoradiography Rattus Regulation Reporting Research Role Sampling Serum-Free Culture Media Slide Source Specificity Staining method Stains T-Lymphocyte TP53 gene TdT-Mediated dUTP Nick End Labeling Assay Testing Time Transferrin Trypan Blue World Health Organization annexin A5 base cell type design immunocytochemistry improved in vivo indexing inhibitor/antagonist innovation member motor impairment mutant myelination nervous system disorder novel null mutation oligodendrocyte precursor precursor cell progenitor pup receptor receptor expression regional difference research study response selective expression white matter

项目摘要

According to The World Health Organization, iron deficiency is the foremost nutritional disorder in the world. Iron is essential for normal neurological function and iron deficiency results in cognitive and motor impairments that can last throughout life, and are often irreversible. Many of the neurological problems associated with iron deficiency can be traced to hypomyelination. The role of iron in myelination was established over the past 20 years, by data from the PI's laboratory revealing that oligodendrocytes stain more prominently than any other cell type in the brain for iron. These data were consistent with the relatively high concentration of iron-requiring enzymes involved in myelination. However, a significant omission in the paradigm regarding iron and oligodendrocyte function, how oligodendrocytes acquire iron, has not been identified. We and others reported that despite the relatively high levels of iron in white matter tracts, there was no detectable transferring receptor (the traditional cellular mechanism for iron acquisition) in white matter. Even when iron deficiency is so severe as to cause hypomyelination, transferring receptor expression in white matter is not detectable. We propose the overall hypothesis that H-ferritin is the iron delivery vehicle for oligodendrocytes instead of transferrin. Recently, a member of the semaphorin family, T-cell immunoglobulin mucin domain 2 (Tim-2) was discovered to bind H-ferritin. Thus, the conceptual framework for this line of research is that Tim-2 is the ferritin binding protein that is selectively expressed by oligodendrocytes and is the mechanism by which these cells obtain the iron that is required to produce and sustain myelin. The significance of the proposed research is that we have found a novel, developmentally regulated, selectively expressed, receptor for iron acquisition on oligodendrocytes. Because the only other known ligand for Tim-2 is Sema4A, a protein expressed on antigen presenting cells and activated Band T lymphocytes, a potentially significant future direction that can be pursued following the studies proposed herein will be to explore the possibility of a connection between the immune system and oligodendrocytes via Tim-2 expression on oligodendrocytes that could affect demyelinating disorders. The project is innovative because the aims are designed to establish the following new data on the role of iron in myelination of eNS: i) H-ferritin is the definitive mechanism by which oligodendrocytes acquire iron; ii) the H-ferritin binding protein on oligodendrocytes is Tim-2, iii) that H-ferritin protein can be used as a delivery vehicle to improve myelination following iron deficiency. The knowledge of how iron is managed and delivered to oligodendrocytes as well as the timing of expression of iron acquisition proteins can be expected to inform intervention strategies for the treatment of developmental hypomyelination resulting from iron deficiency and demyelinating disorders and remyelination attempts in the adult such as Multiple Sclerosis.

根据世界卫生组织的说法，铁缺乏症是世界上最重要的营养障碍。铁对于正常的神经功能和铁缺乏至关重要，导致认知和运动障碍可以持续一生，并且通常是不可逆转的。与铁缺乏症相关的许多神经系统问题都可以追溯到低切术。在过去20年中，通过PI实验室的数据，铁在髓鞘中的作用是在大脑中大脑中的任何其他细胞类型的铁染色更大。这些数据与参与髓鞘的相对较高浓度的铁酶一致。但是，尚未鉴定出有关铁和少突胶质细胞功能的范式的显着遗漏，少突胶质细胞如何获得铁。我们和其他人报告说，尽管白质区中铁的水平相对较高，但在白质中仍未检测到的转移受体（传统的铁收采集机制）。即使铁缺乏症如此严重以至于引起低切髓，也无法检测到白质中的受体表达。我们提出了总体假设，即H-铁蛋白是少突胶质细胞而不是转铁蛋白的铁输送车。最近，发现了信号素家族的T细胞免疫球蛋白粘蛋白结构域2（TIM-2）结合H-铁蛋白。因此，这一研究线的概念框架是TIM-2是铁蛋白结合蛋白，由少突胶质细胞选择性表达，并且是这些细胞获得产生和维持髓磷脂所需的铁的机制。拟议的研究的意义在于，我们发现了一种新型的，发育调节的，有选择性地表达的受体，用于少突胶质细胞的铁。因为TIM-2的唯一其他已知配体是SEMA4A，所以一种在抗原呈现细胞和活化的带T淋巴细胞上表达的蛋白质，在本文提出的研究之后，可以通过Tim-2通过Tim-2对少突击表达的表达来探索可能会探索可能会探索可能会影响少型刺激的可能性，探索本文提出的研究的可能性可能会探索可能实现的可能性重要的未来方向。该项目具有创新性，因为该目标旨在建立以下有关铁在ENS髓鞘中的作用的新数据：i）H-铁蛋白是少突胶质细胞获得铁的确定机制； ii）少突胶质细胞上的H-铁蛋白结合蛋白是TIM-2，iii），H-铁蛋白蛋白可用作递送载体，以改善铁缺乏症后的髓鞘形成。可以期望如何将铁管理和输送到少突胶质细胞进行管理和输送到少突胶质细胞以及铁的表达蛋白质表达的时机，这会为干预策略提供了干预策略，以治疗铁缺乏症和脱髓鞘性疾病和成年人在成年人中的延迟尝试所引起的发育性低下。