miR-324-5p新的靶基因CUEDC2调节巨噬细胞功能和分化的机制研究

Macrophages are key players in the immune system and dysregulation of its function lead to uncontrollable infections, tumor and autoimmune diseases. In a recently study, which published on Nature Immunology in 2010, we have shown a new mechanism of macrophage functional regulation. We found that the pivotal kinase of NF-kappa B signaling pathway, IKK-alpha, has been up-regulated markedly during the monocytes-macrophages differentiation. The elevated IKK-alpha modulates the macrophages' function by inducing larger amount of the p52, which is the key transcriptional factor of non-canonical NF-kappa B signaling pathway. And, with the same system, we also found that in the macrophages' differentiation process, expression of CUEDC2 protein increased significantly. Preliminary studies suggested that it is a key regulator of macrophages' function and modulated by microRNA miR-324-5p during the monocytes-macrophages differentiation. This project is proposed to further study on how does CUEDC2 modulate the differentiation and function of macrophages how and is CUEDC2 regulated by miR-324-5p during cell differentiation. To reveal the main molecular events that CUEDC2 regulating functions of macrophages based on the primary macrophages from both human and mice. Especially with the application of CUEDC2 knockout mice to develop immune related diseases such as IBD model, we would find the association between dysregulation of macrophages function and related diseases. The results will promote the understanding of the precisely regulated inflammation and provide new insights to the macrophages related diseases.

巨噬细胞是机体重要的免疫细胞，其功能异常与感染、肿瘤和自身免疫疾病的发生密切相关。我们在对人原代巨噬细胞的研究中，发现了IKKa激酶调控巨噬细胞激活的新机制（Nature Immunology，2010，第一作者）。近期研究发现在巨噬细胞分化成熟过程中，miR-324-5p表达量下调，使得其靶基因CUEDC2表达量显著上调，并提示该高表达的CUEDC2抑制巨噬细胞的炎性因子分泌。本项目拟在此重要进展基础上，深入分析CUEDC2对巨噬细胞免疫功能和分化的调控作用，研究其被microRNA调控的分子机制。主要研究策略是以人、鼠原代巨噬细胞为研究对象，发现CUEDC2调控巨噬细胞功能的主要分子事件；利用CUEDC2基因敲除小鼠开展IBD等免疫疾病模型研究，揭示巨噬细胞功能异常与疾病关联的新机制。以上努力将有可能促进对巨噬细胞功能精确调控机制的深入认识，并为炎症及自身免疫疾病等的研究提供重要线索。

巨噬细胞是机体重要的免疫细胞，其功能异常与感染、肿瘤和自身免疫疾病的发生密切相关。我们在对人原代巨噬细胞的研究中，发现了IKKa激酶调控巨噬细胞激活的新机制（Nature Immunology，2010，第一作者）。近期研究发现在巨噬细胞分化成熟过程中，蛋白质CUEDC2表达量显著上调，初步发现该过程受miR-324-5p调节，该microRNA表达量在巨噬细胞分化过程中下调，与预期一致。本项目在此重要进展基础上，首先在50例人原代细胞样本和40例小鼠原代细胞样本中，验证了巨噬细胞分化过程中CUEDC2表达水平的变化规律，并深入分析其被microRNA调控的分子机制。主要采取的研究策略是以人、鼠原代巨噬细胞为研究对象，并利用CUEDC2基因敲除小鼠开展初步的巨噬细胞功能调控研究。在验证CUEDC2在巨噬细胞分化过程中的上调现象的基础上，揭示miR-324-5p对CUEDC2的直接调控作用。上述机制发现为进一步深入研究CUEDC2调控巨噬细胞功能和分化提供了重要的线索。