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A versatile reporter for visualization of myelin plasticity in the genetically modified rat

一种多功能报告基因，用于可视化转基因大鼠的髓磷脂可塑性

基本信息

批准号：
10303241
负责人：
Philip J Horner
金额：
$ 44.41万
依托单位：
METHODIST HOSPITAL RESEARCH INSTITUTE
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 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10303241
关键词：
Aging Anatomy Axon Behavior Behavioral Biological Models Biology Birth Brain CSPG4 gene Cell Lineage Cell membrane Cell physiology Cells Cellular Structures Cyclic Nucleotides Development Disease Elements Endocrine Enterobacteria phage P1 Cre recombinase Epigenetic Process Genes Genetic Health Heart Homeostasis Human Imaging Techniques Injury Label Length Link LoxP-flanked allele Membrane Mental disorders Methods Mitotic Modeling Moloney Leukemia Virus Mouse Strains Mus Myelin Myelin Basic Proteins Myelin Sheath Natural regeneration Nervous system structure Neural Conduction Neurosciences Oligodendroglia Physiological Rattus Reporter Reporting Research Retroviral Vector Role Scientist Seminal Site Specificity Structure Synapses System Terminator Codon Testing Tissues Tomatoes Transgenic Organisms Translating Translations Visualization base embryonic stem cell exosome falls flexibility gain of function innovation leukemia virus neurogenesis postnatal development pre-clinical research progenitor promoter regenerative regenerative therapy relating to nervous system tool vector

项目摘要

Abstract Myelin structure is a critical regulator of nerve conduction and an essential factor in axon development and homeostasis. In recent years, a number of seminal observations have dispelled a long-standing dogma that myelin is a static, inflexible structure. Advances in imaging techniques as well as in the methods used to label myelin have revealed that myelin plasticity occurs at the level of wrap number and sheath length during post- natal development, aging, and regeneration after injury. Observations of myelin plasticity indicate a more profound role of myelin axon function, and thereby highlight a critical need for better tools to investigate the mechanisms of myelin formation and remodeling. Here, we propose that the limited availability of tools for myelin reporting has significantly hindered our understanding of myelin biology. Illuminating the mechanisms of myelin plasticity will dramatically impact our understanding of the function of myelin in the nervous system and how myelin contributes to aging, injury, and disease. Our lab and others have developed myelin reporter systems in the mouse, but many of the behavioral and physiological studies that could inform myelin function are better modeled in the rat. The rat nervous system is unique from the mouse in terms of critical elements of behavior, endocrine function, epigenetics, and neurogenesis. Rats are also considered superior for modeling and translating regenerative therapies. We propose to develop a versatile myelin membrane reporter system in the rat capable of discriminating between new and old myelin in the nervous system with spatial and temporal precision. To generate the first myelin reporter rat system, we propose: Aim 1: Develop a rat myelin reporter system and Aim 2: Test the specificity and efficiency of myelin promoters in the rat reporter system. Results from this research will produce a myelin tagging system that will have unique functional advantages for the study of myelin development, myelin regeneration, and myelin in aging.

摘要髓鞘结构是神经传导的关键调节因子，也是轴突发育和发育的重要因素。动态平衡。近年来，一些开创性的观察已经驱散了一个长期存在的教条，即髓鞘是一种静态的、僵硬的结构。成像技术以及用于标记的方法的进展髓磷脂研究表明，髓鞘可塑性发生在髓鞘数目和鞘长度的水平。出生发育、衰老和受伤后的再生。对髓鞘可塑性的观察表明髓鞘轴突功能的深刻作用，从而突出了迫切需要更好的工具来研究髓鞘形成和重塑的机制。在这里，我们认为髓鞘工具的有限可用性报道严重阻碍了我们对髓鞘生物学的理解。阐明髓鞘的作用机制可塑性将极大地影响我们对髓鞘在神经系统中的功能以及如何髓鞘会导致衰老、损伤和疾病。我们的实验室和其他实验室已经开发出髓鞘报告系统小鼠，但许多可以告知髓鞘功能的行为和生理研究更好以老鼠为模型。就行为的关键要素而言，大鼠神经系统与小鼠是独一无二的，内分泌功能、表观遗传学和神经发生。大鼠也被认为是建模和翻译再生疗法。我们建议开发一种多功能的髓鞘膜报告系统大鼠神经系统新旧髓鞘的时空分辨能力精确度。为了建立第一个髓鞘报告大鼠系统，我们建议：目标1：开发大鼠髓鞘报告系统系统和目的2：在大鼠报告系统中测试髓鞘启动子的特异性和有效性。结果来自这项研究将产生一种具有独特功能优势的髓鞘标记系统，用于研究髓鞘髓鞘发育、髓鞘再生和髓鞘衰老。