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Maintenance and Reorganization of Molecular Domains in Myelinated Axons

有髓轴突分子域的维护和重组

基本信息

批准号：
9222814
负责人：
ANNA M TAYLOR
金额：
$ 5.92万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
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：
2015-02-01 至 2018-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9222814
关键词：
Ablation Action Potentials Address Adult Affect Alpha Cell Alternative Splicing Antibodies Axon Behavioral Binding Biochemical Cell Adhesion Molecules Cell surface Cells Data Demyelinating Diseases Demyelinations Deterioration Development Disease Electrophysiology (science)Event Future Gated Ion Channel Genes Genetic Health Individual Inflammatory Ion Channel Gating Lead Maintenance Mammals Molecular Movement Multiple Sclerosis Mus Muscle Muscle function Muscular Atrophy Myelin Neural Conduction Neuroglia Neurons Patients Phenotype Protein Isoforms Ranvier&apos s Nodes Reporting Research Personnel Role Sodium Channel Techniques Therapeutic Time TimeLine Transgenic Mice axonal degeneration design disability improved innovation insight molecular domain mouse model myelination neurofascin neurotransmission nodal protein novel prevent public health relevance repaired restoration voltage young adult

项目摘要

DESCRIPTION (provided by applicant): Intricate molecular interactions between neurons and supporting glia cells are essential for the rapid propagation of action potentials and form the basis for myelinated axons to achieve saltatory conduction. Previously, the cell surface adhesion molecule Neurofascin (Nfasc) has been shown to have a dual-role, essential to the establishment of axonal domains from both the glial and neuronal interface. While the neuron-specific isoform (NF186) is indispensable for clustering of voltage-gated sodium channels at nodes of Ranvier; the glial-specific isoform (NF155) is required for myelinating glial cells to organize the paranode. Although many studies have used mouse models during development to address the roles of NF155 and NF186 in assembling paranodes and nodes, respectively; researchers have only begun to elucidate their roles in the maintenance and long-term health of the myelinated axons. Furthermore, no studies have addressed their potential to reestablish disrupted molecular domains in adults. In this proposal, we seek to define the role of NF155 and NF186 in the maintenance and repair of molecular domains in myelinated axons. We hypothesize that loss of Nfasc from adults leads to a sequential disruption of molecular domains that is reversible during a critical time frame. The proposed studies utilize novel spatio-temporally controlled transgenic mouse models to genetically ablate Nfasc in adult mice and then to re-express Nfasc at various time points. These mice will be evaluated through a combination of immunohistochemical, biochemical, ultrastructual, electrophysiological, and behavioral techniques in the following specific aims: Aim 1: To ascertain the long-term consequences of disrupted paranodal axo-glial junctions and the potential to restore the paranodal domain in myelinated axons. Aim 2: To elucidate the sequence in which the molecular components at nodes of Ranvier disorganize and potentially reorganize in myelinated axons. This innovative approach will lead to a better understanding of the critical time frame in which axo-glial interactions can be repaired and could ultimately aid in the design of future therapies to restore demyelinated axons and increase mobility in demyelinating diseases, such as multiple sclerosis.

描述（由申请人提供）：神经元和支持神经胶质细胞之间复杂的分子相互作用对于动作电位的快速传播至关重要，并构成有髓鞘轴突实现跳跃传导的基础。以前，细胞表面粘附分子神经成束蛋白（Nfasc）已被证明具有双重作用，从神经胶质和神经元界面的轴突域的建立至关重要。神经元特异性亚型（NF 186）对于电压门控钠通道在郎维尔结处的聚集是必不可少的;神经胶质特异性亚型（NF 155）是髓鞘生成神经胶质细胞组织旁阳极所必需的。尽管许多研究在发育过程中使用小鼠模型来解决NF 155和NF 186分别在组装副阳极和节点中的作用，但研究人员才开始阐明它们在有髓轴突的维持和长期健康中的作用。此外，还没有研究涉及它们在成人中重建破坏的分子结构域的潜力。在这个提议中，我们试图确定NF 155和NF 186在有髓轴突分子结构域的维护和修复中的作用。我们假设，Nfasc从成人的损失导致一个连续的破坏分子结构域，这是可逆的，在一个关键的时间框架。提出的研究利用新的时空控制的转基因小鼠模型在成年小鼠中基因消融Nfasc，然后在不同的时间点重新表达Nfasc。这些小鼠将通过免疫组织化学，生物化学，超微结构，电生理学和行为技术的组合进行评估，在以下具体目标：目的1：为了确定破坏的结旁轴-胶质细胞连接的长期后果和恢复有髓鞘轴突中的结旁结构域的潜力。目的2：阐明朗氏结的分子组分在有髓轴突中的紊乱和潜在重组的顺序。这种创新的方法将导致更好地理解轴-胶质细胞相互作用可以修复的关键时间框架，并最终有助于设计未来的治疗方法，以恢复脱髓鞘轴突并增加脱髓鞘疾病（如多发性硬化症）的流动性。