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The role of ERK1/2 MAP kinase signaling in CNS myelination

ERK1/2 MAP 激酶信号在 CNS 髓鞘形成中的作用

基本信息

批准号：
9032547
负责人：
Sharyl Lynne Fyffe-Maricich
金额：
$ 33.22万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2016-08-22
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9032547
关键词：
Adult Affect Auditory Autoimmune Process Axon Behavior Behavioral Biological Assay Birth Brain Stem Brain region Caliber Clinical Cognition Cognitive Cognitive deficits Communication Data Demyelinating Diseases Demyelinations Development Disease Distant Elongation Factor Ensure Experimental Autoimmune Encephalomyelitis Extracellular Signal Regulated Kinases Failure Generations Genetic Growth Health Human Impaired cognition Impairment Individual Injury Left Lesion Lysophosphatidylcholines MAP Kinase Signaling Pathways MAPK1 gene Mediating Mediator of activation protein Mental disorders Mitogen-Activated Protein Kinases Modeling Molecular Motor Multiple Sclerosis Mus Myelin Myelin Proteins Myelin Sheath Nervous System Physiology Neuraxis Neurodegenerative Disorders Neurodevelopmental Disorder Neurons Oligodendroglia Optic Nerve Patients Phosphoric Monoester Hydrolases Process Production Protein Biosynthesis Proteins Reporting Risk Factors Role Series Signal Pathway Signal Transduction Speed Spinal Cord Staging Stem cells System Tamoxifen Testing Therapeutic Thick Time Tissues Toxin Transgenic Mice Translations Up-Regulation axonal degeneration base cognitive function design insight motor deficit mouse model multiple sclerosis patient myelin degeneration myelination new therapeutic target novel therapeutics oligodendrocyte lineage remyelination repaired response transmission process young adult

项目摘要

DESCRIPTION (provided by applicant): Myelin, produced by the concentric wrapping of oligodendrocyte processes, is critical for the effective and timely communication between neurons in distant regions of the brain and spinal cord. During development, oligodendrocytes tailor the thickness of individual myelin sheaths to the diameter of their target axons to ensure appropriate neuronal function. The importance of myelination becomes obvious in demyelinating diseases such as multiple sclerosis (MS) where the eventual failure of myelin repair results in axonal degeneration and subsequent physical impairments. Furthermore, following episodes of demyelination and remyelination that occur early in the disease course of MS, the matching of myelin thickness to axon diameter fails potentially compromising function and leaving axons vulnerable to damage. How oligodendrocytes generate the appropriate thickness of myelin for an axon of defined size is unknown. A comprehensive understanding of the molecules and signaling pathways important for the generation of central nervous system (CNS) myelin is needed in order to design effective therapeutics tailored to enhance myelin repair in MS patients. Recently, we discovered that ERK1/2, key mediators of an evolutionarily conserved signaling pathway, are both necessary and sufficient for the expansion of the myelin sheath during development and following demyelinating injury in the adult mouse CNS. Based on these findings we hypothesize that ERK1/2 are critical regulators of CNS function through their oligodendrocyte-specific role in controlling myelin sheath growth. The proposed studies will use a series of transgenic mouse models with genetic loss or gain of ERK1/2 function to define the functional consequences of ERK1/2-mediated changes in myelin thickness. The use of an inducible system, where ERK1/2 is activated at specific stages of the oligodendrocyte-lineage, will allow us to tease apart both where and when activated ERK1/2 is most beneficial during myelin repair in two different models of demyelinating injury. Finally, we will test the role of important ERK1/2 interacting proteins to elucidate the molecular mechanisms and downstream targets of activated ERK1/2 important for myelin sheath growth. Defining the function of ERK1/2 in myelin sheath expansion will provide new insights to aid in the identification of novel therapeutic targets to promote myelin repair in patients with demyelinating diseases.

描述（由申请人提供）：髓磷脂由少突胶质细胞突起的同心包裹产生，对于大脑和脊髓远端区域的神经元之间有效和及时的沟通至关重要。在发育过程中，少突胶质细胞根据其目标轴突的直径调整单个髓鞘的厚度，以确保适当的神经元功能。髓鞘形成的重要性在多发性硬化症 (MS) 等脱髓鞘疾病中变得显而易见，其中髓鞘修复的最终失败会导致轴突变性和随后的身体损伤。此外，在多发性硬化症病程早期发生脱髓鞘和髓鞘再生后，髓鞘厚度与轴突直径的匹配失败，可能会损害功能并使轴突容易受到损伤。少突胶质细胞如何为确定尺寸的轴突产生适当厚度的髓磷脂尚不清楚。为了设计增强多发性硬化症患者髓磷脂修复的有效疗法，需要全面了解对中枢神经系统 (CNS) 髓磷脂生成至关重要的分子和信号通路。最近，我们发现 ERK1/2 作为进化上保守的信号通路的关键介质，对于成年小鼠中枢神经系统发育过程中和脱髓鞘损伤后髓鞘的扩张是必要且充分的。基于这些发现，我们假设 ERK1/2 通过少突胶质细胞在控制髓鞘生长中的特异性作用而成为中枢神经系统功能的关键调节因子。拟议的研究将使用一系列具有 ERK1/2 功能遗传缺失或获得的转基因小鼠模型来定义 ERK1/2 介导的髓磷脂厚度变化的功能后果。使用诱导系统（其中 ERK1/2 在少突胶质细胞谱系的特定阶段被激活）将使我们能够在两种不同的脱髓鞘损伤模型中的髓鞘修复过程中弄清楚激活 ERK1/2 的时间和地点。最后，我们将测试重要的 ERK1/2 相互作用蛋白的作用，以阐明对髓鞘生长重要的激活的 ERK1/2 的分子机制和下游靶标。定义 ERK1/2 在髓鞘扩张中的功能将为帮助识别新的治疗靶点以促进脱髓鞘疾病患者的髓鞘修复提供新的见解。