The Effects of Aging and Microglia Dysfunction on Remyelination

衰老和小胶质细胞功能障碍对髓鞘再生的影响

• 批准号: 10603320
• 负责人: Genaro Olveda
• 金额: $ 4.77万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10603320
• 关键词: Action Potentials; Address; Adult; Affect; Aging; Agonist; Alzheimer' s Disease; Amyotrophic Lateral Sclerosis; Apoptotic; Axon; Brain; CSPG4 gene; Cell physiology; Cells; Central Nervous System; Cessation of life; Cholesterol; Chronic; Communication; Community Outreach; Complex; DNA Damage; Data; Demyelinations; Detection; Development; Disease; Disease Progression; Environment; Etiology; Excision; Faculty; Failure; Fluorescence; Functional disorder; Generations; Genetic; Goals; Image; Induction of Apoptosis; Knockout Mice; Knowledge; Label; Lasers; Liver X Receptor; Maintenance; Mediating; Medical center; Mentorship; Methods; Microglia; Modeling; Monitor; Multiple Sclerosis; Mus; Myelin; Myelin Sheath; Names; Natural regeneration; Nerve Degeneration; Neurodegenerative Disorders; Neuroglia; Neurons; Neurosciences; Oligodendroglia; Operative Surgical Procedures; Pathology; Pathway interactions; Phagocytes; Phagocytosis; Population; Preparation; Process; Production; Proliferating; Reporting; Research Design; Research Personnel; Resolution; Resources; Specificity; Speed; Structure; Techniques; Testing; Time; Training; Transgenic Mice; Work; age effect; age related; aged; career; cognitive function; experimental study; high resolution imaging; in vivo; in vivo imaging; insight; myelin degeneration; novel; optical imaging; pharmacologic; receptor; remyelination; repaired; response; serial imaging; spatiotemporal; stem cells; targeted treatment; tissue repair; tool; training opportunity; transmission process

Project Summary The myelin sheath is a complex multilamellar structure wrapped around axons, enhancing the speed and efficiency of neuronal processing in the brain. Damage to the myelin sheath, a common insult seen in aging and different diseases, generates cellular debris. Many reports have demonstrated that removal of debris by microglia, the primary phagocyte of the brain, is crucial in facilitating tissue repair. Moreover, failure to remove debris in a rapid and efficient manner has been shown to further disease progression. Thus, it is necessary to investigate the dynamics and the consequences of failed myelin debris clearance in the brain. However, a fundamental gap exists in understanding the microglia dynamics and mechanism mediating myelin debris clearance as current tools do not provide the cellular specificity and spatiotemporal resolution needed. The development of longitudinal high resolution optical imaging and a new targeted inducible model of demyelination has provided the means necessary to capture microglia’s response to myelin debris. These experiments will provide information about the precise cellular dynamics involved in myelin debris clearance in the live brain for the first time. The overarching goal of this proposal is to characterize the precise microglia dynamics involved in myelin debris clearance. The overall hypothesis of this proposal is that myelin debris will trigger the phagocytic response of microglia to begin the clearance process and failure to do so will inhibit subsequent myelin repair. We will achieve this goal and address this hypothesis through the following Specific Aims. Aim 1 will determine the general dynamics of debris clearance by microglia and the remyelination process by monitoring microglia engagement and the generation of new myelin sheaths. Aim 2 will determine the dynamics of defective debris clearance and its contribution to failed remyelination. Aim 3 will determine the effects of aging on microglia’s ability to clear myelin debris and the remyelination process. Using high resolution in vivo imaging, a novel method of demyelination, and genetic and pharmacological manipulations, these experiments will describe the precise microglia dynamics involved in debris clearance and remyelination. This proposed work has broad implications as defective debris removal is a common etiology for failed myelin repair seen in neurodegenerative diseases and late stages of aging. Working closely with my sponsor and co-sponsor we have developed a rigorous training plan consisting of both technical (in vivo imaging and chronic surgical preparations) and professional (scientific communication, research design, mentorship, and community outreach) training. Dartmouth and Dartmouth Hitchcock Medical Center provide a rich intellectual environment by hosting world class faculty, providing additional resources and training opportunities that are essential for a successful career as an independent researcher in neuroscience.

项目概要 髓鞘是一种复杂的多层结构，包裹着轴突，提高了速度 以及大脑神经处理的效率。髓鞘损伤是常见的损伤。 衰老和不同的疾病会产生细胞碎片，许多报告已证明清除碎片。 小胶质细胞（大脑的主要吞噬细胞）对促进组织修复至关重要。 以快速有效的方式清除碎片已被证明可以进一步促进疾病进展。 对于研究大脑中髓鞘碎片清除失败的动力学和后果是必要的。 然而，在了解小胶质细胞动力学和介导髓鞘质的机制方面存在根本差距 碎片清除，因为当前的工具无法提供所需的细胞特异性和时空分辨率。 纵向高分辨率光学成像的发展和新的靶向诱导模型 脱髓鞘提供了捕获小胶质细胞对髓磷脂碎片的反应所必需的手段。 实验将提供有关髓鞘碎片清除所涉及的精确细胞动力学的信息 该提案的首要目标是精确描述小胶质细胞的特征。 该提案的总体假设是髓磷脂碎片清除。 将触发小胶质细胞的吞噬反应以开始清除过程，否则将抑制 随后的髓磷脂修复，我们将实现这一目标，并通过以下具体内容来解决这一假设。 目标 1 将确定小胶质细胞碎片清除和髓鞘再生的一般动态。 目标 2 将通过监测小胶质细胞参与和新髓鞘的生成来确定这一过程。 碎片清除缺陷的动态及其对髓鞘再生失败的影响将决定目标 3。 衰老对小胶质细胞清除髓磷脂碎片的能力和髓鞘再生过程的影响。 分辨率体内成像、脱髓鞘的新方法以及遗传和药理学操作， 这些实验将描述参与碎片清除和髓鞘再生的精确小胶质细胞动力学。 这项拟议的工作具有广泛的影响，因为碎片清除缺陷是髓鞘质失效的常见病因 修复见于神经退行性疾病和衰老晚期。 我们与我的赞助商和共同赞助商密切合作，制定了严格的培训计划，其中包括 技术（体内成像和慢性手术准备）和专业（科学 沟通、研究设计、指导和社区外展）培训。 希区柯克医疗中心拥有世界一流的教职人员，提供丰富的智力环境， 额外的资源和培训机会对于独立人士的成功职业生涯至关重要 神经科学研究人员。