The Role of PU.1 in Homeostasis and Function of Brain Macrophages

PU.1 在脑巨噬细胞稳态和功能中的作用

• 批准号: 165157194
• 负责人: Professor Dr. Frank Rosenbauer
• 金额: --
• 依托单位: Institut für Medizinische Informatik
• 依托单位国家: 德国
• 项目类别: Research Units
• 财政年份: 2010
• 资助国家: 德国
• 起止时间: 2009-12-31 至 2015-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/165157194?language=en
• 关键词: Role; PU.1; Homeostasis; Function; Brain

The PU.1 transcription factor is essential for the differentiation of hematopoietic stem cells into early myeloid progenitors, but its role in mature myeloid cells is poorly understood. To elucidate whether PU.1 is required for macrophage homeostasis in the brain, we have generated a mouse model in which the PU.1 gene can be inductively deleted in macrophages using the myeloid-specific CX3CR1GFP-ERT-Cre allele. Unexpectedly, our preliminary data suggest that PU.1 ablation leads to an expanded rather than reduced brain macrophage compartment, and skews peripheral blood myeloid cells towards inflammatory monocytes. In the upcoming funding period, we aim on extending our investigation of the functional role of PU.1 in adult macrophage homeostasis, with a particular focus on macrophages of the brain. Moreover, we will explore whether PU.1 controls macrophage function during a pathological scenario within the central nervous system. Finally, we will use genome-wide technologies to identify PU.1 target genes and PU.1-occupied chromatin sites in brain macrophages, and will compare these data with those of macrophages from another tissue. Taken together, these experiments will provide important novel insight into the mechanistic regulation of brain macrophage homeostasis and function.

PU.1转录因子是造血干细胞向早期髓系祖细胞分化所必需的，但其在成熟髓系细胞中的作用尚不清楚。为了阐明脑内巨噬细胞稳态是否需要PU.1，我们建立了一个小鼠模型，在该模型中，PU.1基因可以通过骨髓特异性CX3CR1GFP-ERT-Cre等位基因在巨噬细胞中被诱导删除。出乎意料的是，我们的初步数据表明，PU.1消融导致脑巨噬细胞室扩大而不是缩小，并使外周血骨髓细胞向炎性单核细胞倾斜。在即将到来的资助期内，我们的目标是扩展我们对PU.1在成人巨噬细胞稳态中的功能作用的研究，特别关注大脑的巨噬细胞。此外，我们将探讨在中枢神经系统的病理情况下，PU.1是否控制巨噬细胞的功能。最后，我们将使用全基因组技术鉴定脑巨噬细胞中PU.1靶基因和PU.1占据的染色质位点，并将这些数据与来自其他组织的巨噬细胞的数据进行比较。综上所述，这些实验将为脑巨噬细胞稳态和功能的机制调节提供重要的新见解。