Proliferation and differentiation of adult microglia progenitor cells

项目总结/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。 MG是中枢神经系统中的特化常驻髓样细胞，在先天性免疫应答中发挥重要作用。 CNS局部缺血和创伤性脑损伤（TBI）引起循环免疫细胞的募集和免疫球蛋白的活化。 常驻MG激活的MG执行动态功能，对神经元既可以是支持性的，也可以是破坏性的。 健康MG在CNS发育、可塑性和免疫监视中也具有重要作用。然而 成人CNS中MG的个体发生仍不完全清楚。当MG祖细胞定居在 发育中的脑在胚胎卵黄囊中出生，最近的报道表明MG祖细胞是 也存在于成人CNS中。当成年MG被耗尽时，这些祖细胞分裂并分化为 成年MG这些发现表明MG可塑性不仅涉及分子和形态学 改变现有的细胞，而且还产生了新的MG群体。目前，我们对 MG祖细胞在正常、老化或受损大脑中的潜在作用。我们有兴趣了解 MG行为的调节，包括急性期和急性期新生MG的产生和分化， 慢性中枢神经系统损伤和神经退行性变。我们已经开发了分离和培养MG祖细胞的方法 成年小鼠脑细胞。这种祖细胞群存在于未受伤的成年CNS中，可以分离得到， 通过细胞分选或阳性选择，并将在体外分化为成熟MG。本提案的目标 是为了确定如何新生MG有助于成熟MG人口的背景下， 以确定区分MG祖细胞和MG祖细胞的分子途径， 成熟MG我们拟研究衰老小鼠MG再增殖的过程，以确定年龄是否 影响成年CNS驻留的红细胞样前体细胞、MG祖细胞、 细胞和成熟MG。我们将采用这种方法来确定阿尔茨海默病的APP/PS1小鼠模型是否 疾病（AD）影响祖细胞和成熟MG群体的大小。此外，为了确定 为了获得MG祖细胞的特异性分子标记，我们将通过离体流式细胞术分离祖细胞和成熟MG， 使用流式细胞术检测三个群体的基因表达谱，并使用RNA测序比较三个群体的总体基因表达谱。在 总之，这些目标的实现将有助于进一步了解调节蛋白质表达的分子信号。 MG及其祖细胞在CNS内。

PROJECT SUMMARY/ABSTRACT Neuroinflammation plays a critical role in injury and degeneration in the central nervous system (CNS). MG are specialized resident myeloid cells in the CNS that play essential roles the innate immune response. CNS ischemia and traumatic brain injury (TBI) cause recruitment of circulating immune cells and activation of resident MG. Activated MG perform dynamic functions that can be both supportive and destructive to neuronal health. MG also have essential roles in CNS development, plasticity and immune surveillance. However the ontogeny of MG in the adult CNS is still not fully understood. While MG progenitors that colonize the developing brain are born in the embryonic yolk sac, recent reports demonstrate that MG progenitor cells are also present in the adult CNS. When adult MG are depleted, these progenitor cells devide and differentiate into mature adult MG. These findings suggest that MG plasticity not only refers to the molecular and morphological changes of existing cells, but also the generation of a new MG populations. Currently, little is known regarding the potential role for MG progenitors in the normal, aging or injured brain. We are interested in understanding the regulation of MG behavior, including the generation and differentiation of newly born MG during acute and chronic CNS injury and neurodegeneration. We have developed methods to isolate and culture MG progenitor cells from adult mouse brain. This progenitor population is present in the uninjured adult CNS, can be isolated by cell sorting or positive selection and will differentiate into mature MG in vitro. The goals of this proposal are to determine how newly born MG contribute to the mature MG population in the setting of advanced age or disease and to identify molecular pathways that distinguish MG progenitors from mature MG. We propose to study the process of MG repopulation in aging mice and to determine whether age influences the rate of cellular proliferation in adult CNS resident erythromeyloid precursor cells, MG progenitor cells and mature MG. We will employ this approach to determine if the APP/PS1 mouse model of Alzheimer's disease (AD) influences the size of the progenitor and mature MG populations. In addition, to determine the specific molecular signature of MG progenitors cells, we will isolate progenitors and mature MG by ex-vivo flow cytometry and compare the global gene expression profiles of the three populations using RNA sequencing. In summary, the accomplishment of these aims will help to further understand the molecular signals that regulate MG and their progenitors within the CNS.