Method for Large-scale Quantitative Analysis of Myelin in Living Animals

活体动物髓磷脂的大规模定量分析方法

• 批准号: 9208294
• 负责人: Hyungsik Lim
• 金额: $ 33.84万
• 依托单位: HUNTER COLLEGE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9208294
• 关键词: Action Potentials; Affect; Animal Model; Animals; Axon; Basic Science; Brain; Caliber; Cell Communication; Cephalic; Cerebral cortex; Cerebrum; Chelating Agents; Clinical; Cognitive deficits; Computing Methodologies; Copper; Cuprizone; Demyelinations; Detection; Development; Diagnosis; Diet; Disease; Electron Microscopy; Evaluation; Fiber; Fluorescence; Fluorescent Dyes; Generations; Image; Imagery; Investigation; Knowledge; Label; Measures; Membrane; Methods; Microscopy; Modality; Modeling; Morphology; Multiple Sclerosis; Multiple Sclerosis Lesions; Mus; Myelin; Myelin Sheath; Nerve; Nerve Degeneration; Nerve Tissue; Nervous system structure; Neuraxis; Neuroglia; Neurons; Optical Methods; Optics; Pathogenicity; Pathology; Peripheral; Peripheral Nerves; Peripheral Nervous System; Process; Property; Research; Resolution; Sampling; Specificity; Specimen; Staining method; Stains; Statistical Methods; Statistical Models; Structure; Techniques; Technology; Testing; Thick; Thinness; Time; Tissue Sample; Tissues; Transgenic Mice; Translational Research; biophysical model; brain tissue; cell type; central nervous system demyelinating disorder; clinically significant; cortex mapping; feeding; imaging capabilities; imaging modality; improved; in vivo; innovation; interest; light microscopy; markov model; microscopic imaging; morphometry; myelination; nanometer; neural information processing; novel; prevent; remyelination; restoration; sample fixation; scale up; sensor; translational medicine; two-photon

Abstract Multiple sclerosis (MS) is a demyelinating disease of the central nervous system affecting more than 2.3 million people worldwide. The pathogenic mechanism is not well understood and the diagnosis does not occur early enough to prevent further neurodegeneration. Evidence suggests that demyelination in the cerebrum is an important lesion of MS correlating well with cognitive defects in the disease. However, the clinical significance has not been fully established because cortical myelin cannot be observed in vivo over a long period. Here we propose to develop optical methods for studying cortical myelin in living animals. A new imaging modality will be employed, namely third-harmonic generation microscopy (THGM), which we recently demonstrated for label-free visualization of myelin in intact nerves of the peripheral nervous system. Powerful imaging capabilities will be developed suitable for advancing our knowledge of cortical myelination. First, THGM will be validated for probing cortical demyelination and remyelination in living MS animal models. Second, wavefront control will be implemented to facilitate large-scale THGM imaging of cortical myelin in deep mouse brain. Third, super-resolution THGM morphometry will be achieved by image restoration and probabilistic modeling. Upon successful completion, this project will open a new field of investigations in basic science as well as translational medicine to elucidate the axon-glial cell interaction underlying cortical demyelination and remyelination.

抽象的 多发性硬化症 (MS) 是一种中枢神经系统脱髓鞘疾病，影响超过 230 万人 世界各地的人们。发病机制尚不清楚，不能及早诊断 足以防止进一步的神经退行性变。有证据表明，大脑脱髓鞘是一种 MS 的重要病变与该疾病的认知缺陷密切相关。但临床意义 由于无法在体内长期观察到皮质髓磷脂，因此尚未完全确定。在这里我们 提议开发光学方法来研究活体动物的皮质髓磷脂。一种新的成像方式将 被采用，即三次谐波发生显微镜（THGM），我们最近证明了 周围神经系统完整神经中髓磷脂的无标记可视化。强大的成像能力 将开发适合增进我们对皮质髓鞘形成知识的能力。首先，THGM 将 经验证可在活体多发性硬化症动物模型中探测皮质脱髓鞘和髓鞘再生。二、波前 将实施控制以促进小鼠大脑深处皮质髓磷脂的大规模 THGM 成像。 第三，超分辨率THGM形态测量将通过图像修复和概率建模来实现。 成功完成后，该项目将开辟基础科学的新研究领域以及 转化医学阐明皮质脱髓鞘背后的轴突-神经胶质细胞相互作用 髓鞘再生。