Identification of factors regulating fate and function of microglia and macrophages in the CNS.

大脑承载着一个异质性的髓细胞群，包括实质小胶质细胞（MG）、血管周围和脑膜巨噬细胞和脉络膜丛巨噬细胞(M)。除了发育过程中的功能外，髓细胞在几乎所有中枢神经系统疾病中都起着至关重要的作用，髓细胞功能障碍被认为是一组称为小胶质病的疾病的病因。我们将采用新的遗传和成像方法在单细胞水平上阐明骨髓细胞的命运、多样性和功能。我的建议有三种主要方法作为支撑：首先（目标1），我们将挑战关于M.的起源和命运的经典的少数观点。这些细胞被认为是短命的，与卵黄囊衍生的MG细胞相反，它们来自循环细胞。我们的初步数据显示了一个完全相反的观点，并假设一个不同的谱系。其次（目标2），在健康和疾病期间，MG和M网络的动力学和动力学将通过使用一种新的多色荧光命运映射系统在体内进行检查，这将为细胞稳态和更新提供新的见解。第三（目标3），MG和M中独特的遗传特征被认为是它们多样化生物学功能的基础。通过大规模并行单细胞RNAseq，我们将揭示它们在稳态单细胞水平上的异质性。我们期望我们的结果将从根本上改变我们对髓细胞的传统看法。

The brain hosts a heterogeneous population of myeloid cells, including parenchymal microglia (MG), perivascular & meningeal macrophages and choroid plexus macrophages (M). In addition to functions during development myeloid cells are crucially involved in virtually all CNS diseases and myeloid dysfunction is thought to be causal for a group of diseases, called microgliopathies. Novel genetic and imaging methodologies will be employed by us to elucidate myeloid cell fate, diversity and function on single cell level. My proposal is pillared by three main approaches: First (Aim 1), we will challenge the classical few on the origin and fate of M. These cells are thought to be short lived and to derive, in contrast to yolk sac-derived MG , from circulating cells. Our prelimary data suggest a complete opposing view and suppose a different lineage. Second (Aim 2), kinetics and dynamics of MG & M networks during health and disease will be examined in vivo by using a new multicolour fluorescence fate mapping system that will provide new insights into cell homeostasis and renewal. Third (Aim 3), a distinct genetic signature in MG & M is thought to be the basis of their diverse biological functions. By applying massively parallel single cell RNAseq we will uncover their heterogeneity on single cell level in steady state. We expected that our results will fundamentally change our traditional view on brain myeloid cells.