Development and validation of a multimodal MRI/near-infrared spectroscopysystem to study brain oxidative metabolism in mouse models of neurologicaldisease

开发和验证多模态 MRI/近红外光谱系统，用于研究神经系统疾病小鼠模型的脑氧化代谢

• 批准号: 9326993
• 负责人: Jeffrey Frank Dunn
• 金额: $ 14.74万
• 依托单位: UNIVERSITY OF CALGARY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9326993
• 关键词: Age; Alzheimer' s Disease; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Apoptosis; Atrophic; Autistic Disorder; Autoimmune Responses; Belief; Brain; Brain Diseases; Canada; Cell Respiration; Chronic; Computer software; Country; Cuprizone; Data; Data Collection; Defect; Demyelinations; Development; Disease; Disease Progression; Disease model; Elements; Foundations; Geometry; Grant; Head; Health system; Hemoglobin; Hypoxia; Impairment; Incidence; Inflammation; International; Knowledge; Light; Link; Magnetic Resonance Imaging; Measurement; Measures; Metabolic; Methods; Mitochondria; Modeling; Multiple Sclerosis; Mus; Near-Infrared Spectroscopy; Neurology; Oligodendroglia; Oxidation-Reduction; Oxygen; Oxyhemoglobin; Patients; Penetration; Perfusion; Physiologic pulse; Physiological; Physiology; Pre-Clinical Model; Preclinical Testing; Reproducibility; Research; Scientist; Societies; Specialist; Spinal Diseases; Symptoms; System; Technology; Time; Validation; Venous; behavior test; brain metabolism; cerebral oxygenation; cohort; cost; cytochrome c oxidase; disabling disease; gray matter; histological studies; imaging scientist; in vivo; metabolic rate; mild traumatic brain injury; mitochondrial dysfunction; mouse model; multimodality; nervous system disorder; neuropathology; new technology; novel; portability; pre-clinical; tool; white matter

Neurological diseases are a significant and increasing burden on our society. These include multiple sclerosis (MS), autism, Alzheimer's disease, mild traumatic brain injury etc. Many are associated with age. These diseases have a high societal impact in terms of cost to patients and the health system. Damaged mitochondria and oxidative metabolism are often implicated. There are few methods available to study mitochondrial function in living brain. Since mouse is the main preclinical model, and oxidative metabolism is high in gray matter (GM), we will develop methods specifically targeted to the difficult task of studying oxidative metabolism in vivo in mouse cortical gray matter. This project is to integrate, optimize and show proof of principle for a new multimodel MRI/near-infrared spectroscopy method for studying oxidative metabolism and mitochondrial function in gray matter of mouse models of neurological disease. Using a mouse model of multiple sclerosis for proof of principle, we will gain new knowledge of the relationships between mitochondrial damage, hypoxia, oxidative metabolism, and demyelination. In Aim 1, we will integrate and the MRI/NIRS system using geometries appropriate for mouse brain gray matter. Perfusion will be quantified using MRI; arterial oxygen saturation with a pulse oximeter; and microvascular oxygen saturation, venous hemoglobin saturation and total hemoglobin from broadband NIRS (to calculate GM CMRO2) Hemoglobin saturation provides a hypoxia marker. We will introduce cytochrome oxidase Cua redox data collection to assess mitochondrial redox, model light penetration in the mouse head to optimize for gray matter, integrate the data collection to one portable software package and determine reproducibility in a cohort of mice. In Aim 2, as proof of principle, we will study the cuprizone mouse model of MS. The model is demyelinating, has damaged mitochondria and hypoxia has been suggested to occur. Current treatments in MS focus on inflammation and demyelination but axonal loss and atrophy still occur. There may be a defect in mitochondrial function. We will show how CMRO2, perfusion, hypoxia and mitochondrial redox status are related to demyelination and symptoms. We will develop an MRI/NIRS system for assessing oxidative metabolism in gray matter of mouse models of neurological disease opening up new avenues of research to study the interplay between mitochondrial damage, oxidative metabolism, perfusion and hypoxia. We will show proof of principle by obtaining new and novel data showing how oxidative metabolism relates to demyelination in a mouse model of MS.

神经系统疾病是我们社会的一个重大和日益增加的负担。这些包括 多发性硬化症（MS），自闭症，阿尔茨海默病，轻度创伤性脑损伤等。 与年龄有关。这些疾病在对患者的成本方面具有很高的社会影响， 卫生系统。受损的线粒体和氧化代谢往往牵连。很少 研究活体脑线粒体功能的方法。由于小鼠是主要的临床前研究 模型，氧化代谢在灰质（GM）中很高，我们将专门开发方法 目标是在小鼠皮质灰质中研究体内氧化代谢的困难任务。 这个项目是整合，优化和展示一个新的多模型的原理证明 一种研究氧化代谢和线粒体的MRI/近红外光谱方法 神经系统疾病小鼠模型的灰质功能。使用小鼠模型， 多发性硬化症的原理证明，我们将获得新的知识的关系， 线粒体损伤缺氧氧化代谢和脱髓鞘之间的联系 在目标1中，我们将使用适合于小鼠的几何形状来集成MRI/NIRS系统 大脑灰质。将使用MRI定量灌注;脉搏动脉血氧饱和度 血氧计;微血管血氧饱和度、静脉血红蛋白饱和度和总血红蛋白 从宽带NIRS（以计算GM CMRO 2）血红蛋白饱和度提供缺氧标记。 我们将介绍细胞色素氧化酶Cua氧化还原数据收集，以评估线粒体氧化还原，模型 光穿透鼠标头部以优化灰质，将数据收集整合到一个 便携式软件包，并确定小鼠队列中的再现性。 在目标2中，作为原理的证明，我们将研究MS的cuprizone小鼠模型。 脱髓鞘已经损害了线粒体，并且已经表明发生了缺氧。电流 MS的治疗集中于炎症和脱髓鞘，但轴突损失和萎缩仍然发生。 线粒体功能可能有缺陷。我们将展示CMRO 2、灌注、缺氧和 线粒体氧化还原状态与脱髓鞘和症状有关。 我们将建立一套MRI/NIRS系统，用于评价小鼠脑灰质的氧化代谢 神经系统疾病的模型开辟了新的研究途径，研究 线粒体损伤、氧化代谢、灌注和缺氧。我们会证明原则 通过获得新的和新颖的数据，显示氧化代谢如何与脱髓鞘相关， MS小鼠模型。