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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.

抽象的髓磷脂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。体内平衡。近年来，一些开创性的观察结果消除了长期存在的教条：髓磷脂是一种静态的、缺乏弹性的结构。成像技术以及标记方法的进步髓磷脂揭示了髓磷脂可塑性发生在后包裹数和鞘长度的水平上。出生时的发育、衰老和受伤后的再生。对髓磷脂可塑性的观察表明髓磷脂轴突功能的深远作用，从而凸显了对更好的工具来研究的迫切需要髓磷脂形成和重塑的机制。在这里，我们建议髓鞘质工具的可用性有限报告极大地阻碍了我们对髓磷脂生物学的理解。阐明髓磷脂的机制可塑性将极大地影响我们对神经系统中髓磷脂功能及其作用的理解髓磷脂会导致衰老、损伤和疾病。我们的实验室和其他人开发了髓磷脂报告系统小鼠，但许多可以了解髓磷脂功能的行为和生理研究更好以大鼠为模型。就行为的关键要素而言，大鼠神经系统与小鼠不同，内分泌功能、表观遗传学和神经发生。老鼠也被认为在建模和翻译再生疗法。我们建议开发一种多功能髓磷脂膜报告系统大鼠能够通过空间和时间区分神经系统中的新髓磷脂和旧髓磷脂精确。为了生成第一个髓磷脂报告基因大鼠系统，我们建议：目标 1：开发大鼠髓磷脂报告基因系统和目标 2：测试大鼠报告系统中髓磷脂启动子的特异性和效率。结果来自这项研究将产生一种髓磷脂标记系统，该系统对于研究髓鞘质具有独特的功能优势。髓磷脂发育、髓磷脂再生和髓磷脂衰老。