Microglia ontogeny, proliferation and maturation in Alzheimer's Disease

阿尔茨海默病中小胶质细胞的个体发育、增殖和成熟

• 批准号: 10092493
• 负责人: GWENN A GARDEN
• 金额: $ 40.37万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-15 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10092493
• 关键词: Microglia; ontogeny; proliferation; maturation; Alzheimer

PROJECT ABSTRACT: Neuroinflammation plays a critical role in injury and degeneration in the central nervous system (CNS). Microglia (MG) are specialized resident myeloid cells in the CNS that play essential roles the innate immune response. MG also have essential roles in CNS development, plasticity and immune surveillance. CNS injury and neurodegeneration lead to inflammatory activation of MG. Activated MG perform dynamic functions that can be both supportive and destructive to neuronal health. In the adult CNS MG turnover occurs very slowly but new MG can be rapidly generated after depopulation or in response to injury. However the ontogeny of new MG in the adult CNS is still not fully understood. While MG progenitors (MGP) that colonize the developing brain are born in the embryonic yolk sac, recent reports suggest that MGP cells may also exist in the adult CNS. Thus MG plasticity may not only refer to the molecular and morphological changes of existing cells, but also the generation of new MG populations. Currently, little is known regarding the potential role of newly born microglia in Alzheimer's disease (AD). We are interested in understanding the regulation of MG behavior, including the generation and differentiation of newly born MG in the setting of neurodegeneration. We have developed novel methods to fate map and isolate a population of cells expressing both markers of progenitor state (prominin 1) and myeloid commitment (Cd45) from the adult mouse brain. This potential progenitor population is present in the uninjured adult CNS, can be isolated by fluorescence activated cell sorting (FACS) and will differentiate into mature MG in vitro and in vivo. The goals of this proposal are to 1) determine if AD pathology influences the proliferation, differentiation, and survival of newly born MG in the adult CNS, 2) to determine if MGP contribute to the microglia population associated with amyloid plaque, 3) examine whether AD pathology influences the epigenetic profile and transcriptome of adult MGP and 4) determine if the inflammatory activation pattern in MGP derived mature microglia is influenced by cellular age or origin. We will employ mouse models of AD that develop early amyloid plaque to determine if these pathological hallmarks of AD influence the population dynamics of the progenitor and mature MG populations. In addition, we plan to employ state of the art single cell sequencing approaches to study how AD pathology influences chromatin architecture and gene expression in these distinguishable populations of CNS myeloid cells. In summary, the accomplishment of these aims will help to further understand dynamics of MG populations and the influence of those population dynamics on the inflammatory response in AD brain.

项目摘要： 神经炎症在中枢神经系统（CNS）的损伤和变性中起关键作用。 小胶质细胞（MG）是中枢神经系统中的特化常驻髓样细胞，在先天性免疫中发挥重要作用 反应MG在CNS发育、可塑性和免疫监视中也具有重要作用。CNS损伤 和神经变性导致MG的炎性激活。激活的MG执行动态功能， 对神经元的健康既有利又有害。在成年CNS中，MG的周转非常缓慢 但新的MG可在种群减少后或对损伤的反应中迅速产生。然而， 成人中枢神经系统中新的MG仍不完全清楚。而MG祖细胞（MGP），殖民的 发育中的大脑是在胚胎卵黄囊中出生的，最近的报道表明MGP细胞也可能存在于胚胎卵黄囊中。 成人中枢神经系统。因此，MG可塑性可能不仅指存在的分子和形态的变化， 细胞，但也产生新的MG群体。目前，人们对的潜在作用知之甚少 阿尔茨海默病（AD）中新生的小胶质细胞。我们有兴趣了解MG的监管 行为，包括在神经变性的情况下新生MG的产生和分化。 我们已经开发了新的方法来命运映射和分离表达两种标记物的细胞群体， 祖细胞状态（CD41）和髓样定型（Cd45）。这种潜在 祖细胞群存在于未损伤的成年CNS中，可以通过荧光激活细胞分离 细胞分选（FACS），并将在体外和体内分化为成熟MG。本提案的目标是：（1） 确定AD病理学是否影响新生MG的增殖、分化和存活， 2）确定MGP是否有助于与淀粉样蛋白相关的小胶质细胞群体 斑块，3）检查AD病理是否影响成年人的表观遗传谱和转录组。 MGP和4）确定MGP衍生的成熟小胶质细胞中的炎性活化模式是否是 受细胞年龄或起源的影响。我们将采用AD小鼠模型， 以确定AD的这些病理学标志是否影响祖细胞的群体动态， 成熟MG人群。此外，我们计划采用最先进的单细胞测序方法， 研究AD病理如何影响这些可区分的细胞中的染色质结构和基因表达， CNS髓样细胞群。总之，实现这些目标将有助于进一步 了解MG群体的动态以及这些群体动态对炎症的影响， AD大脑的反应。