The Effects of Aging and Microglia Dysfunction on Remyelination

项目摘要 髓鞘是一种复杂的多层结构，包裹着轴突， 和大脑中神经元处理的效率。髓鞘损伤，这是一种常见的损伤， 老化和不同的疾病，产生细胞碎片。许多报告表明， 小胶质细胞是大脑的主要吞噬细胞，它对促进组织修复至关重要。此外，未能 以快速和有效的方式去除碎片已经显示出进一步的疾病进展。照经上所 有必要研究动力学和后果失败的髓鞘碎片清除在大脑中。 然而，在理解小胶质细胞的动力学和介导髓鞘的机制方面存在根本性的差距 作为当前工具的碎片清除不能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鞘碎片的反应所必需的手段。这些 这些实验将提供关于参与髓鞘碎片清除的精确细胞动力学的信息， 这是第一次活的大脑。这项提案的首要目标是描述精确的小胶质细胞 动力学参与髓鞘碎片清除。这项提议的总体假设是， 将触发小胶质细胞的吞噬反应以开始清除过程 随后的髓鞘修复。我们将通过以下具体步骤来实现这一目标并解决这一假设 目标。目的1将确定小胶质细胞清除碎片的一般动力学和髓鞘再生 通过监测小胶质细胞的参与和新髓鞘的产生来监测这一过程。目标2将决定 缺陷碎片清除的动力学及其对髓鞘再生失败的贡献。目标3将决定 衰老对小胶质细胞清除髓鞘碎片和髓鞘再生过程的影响。使用高 分辨率体内成像，脱髓鞘的新方法，以及遗传和药理学操作， 这些实验将描述涉及碎片清除和髓鞘再生的精确的小胶质细胞动力学。 这项工作具有广泛的意义，因为有缺陷的碎片清除是失败的髓鞘的常见病因 在神经退行性疾病和衰老后期出现的修复。 与我的赞助商和共同赞助商密切合作，我们制定了严格的培训计划， 技术（体内成像和慢性手术准备）和专业（科学 交流、研究设计、指导和社区外展）培训。达特茅斯和达特茅斯 希区柯克医疗中心提供了一个丰富的智力环境主办世界一流的教师，提供 额外的资源和培训机会，这是一个成功的职业生涯作为一个独立的 神经科学研究员

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.