Identification of novel microglial signaling routes triggered by extracellular microRNAs and their impact on glioma

小胶质细胞是大脑中的主要免疫细胞，在脑内稳态和疾病中都能感知内在和宿主衍生的因子，这些因子以复杂的方式控制它们的表型。在这里，我们研究了一组新的此类因素，即microRNAs(MiRNAs)。最近发现，这些小的非编码的、基因调控的RNA在大脑中大量表达，可以作为小胶质细胞表达的免疫受体Toll样受体7和8的配体。MiRNAs在细胞间转移，并在血液和脑脊液等体液中循环。在此基础上，我们提出了一种新的机制，通过序列特异性地结合miRNAs和小胶质细胞受体来调节小胶质细胞的功能。该项目的目的是：i)确定小胶质细胞中表达的miRNA传感受体的谱系；ii)评估miRNAs通过与相应的受体结合来改变小胶质细胞功能的潜力；iii)确定细胞外miRNA与小胶质细胞受体之间的相互作用在中枢神经系统疾病(如成人最恶性的脑肿瘤--胶质母细胞瘤)中的作用。破译miRNAs作为小胶质细胞序列特异性信号分子的作用模式，可能为开发各种中枢神经系统疾病的新诊断和治疗策略开辟道路，如GBM。

Microglia, the major immune cells in the brain, sense intrinsic and host-derived factors in both brain homeostasis and disease, which control their phenotype in a complex fashion. Here, we study a new group of such factors, namely microRNAs (miRNAs). It was recently discovered that these small non-coding, gene-regulating RNAs abundantly expressed in the brain, can act as ligands for the immune receptors Toll-like receptor 7 and 8 expressed in microglia. miRNAs are transferred from cell to cell and circulate in body fluids such as blood and cerebrospinal fluid. Based on this, we propose a novel mechanism of regulation of microglial function through sequence-specific binding of miRNAs to microglial receptors. The project’s aim is i) to identify the repertoire of miRNA-sensing receptors expressed in microglia, ii) to assess the potential of miRNAs to modify microglial function through binding to the respective receptor, and iii) to determine the contribution of the interaction between extracellular miRNA and microglial receptors to central nervous system (CNS) diseases such as glioblastoma (GBM), the most malignant brain tumor in adults. Deciphering the miRNAs’ mode of action as sequence-specific signaling molecules for microglia may open the way to the development of new diagnostic and therapeutic strategies in various CNS diseases, such as GBM.