可逆泛素化介导的细胞自噬对非可控炎症的调控作用机制研究

项目名称： 可逆泛素化介导的细胞自噬对非可控炎症的调控作用机制研究

项目编号： No.91629101

项目类型： 重大研究计划

立项/批准年度： 2017

项目学科： 生物科学

项目作者： 崔隽

作者单位： 中山大学

项目金额： 94万元

中文摘要： 非可控炎症在肿瘤的发病进程和恶性转化中起关键作用。大量研究揭示细胞自噬与肿瘤等诸多生理病理过程密切相关。最近的研究发现细胞自噬可能参与调控非可控炎症的信号通路，许多关键炎症调控分子可通过选择性自噬降解。然而，自噬与非可控炎症及其恶性转化的关系尚不明确；由货物识别受体介导的选择性自噬降解对关键炎症分子的特异性调控的分子机制也远未被阐明。我们前期的研究揭示了可逆泛素化参与自噬对炎症反应的特异性调控，并发现TRIM11、USP19等泛素修饰分子在介导自噬和炎症调控交联中的关键作用。在本项目中，我们将结合免疫学，分子生物学和计算生物学方法，系统研究自噬在炎症激活过程中的作用和动态调控规律，绘制细胞自噬多层次调控非可控炎症的分子网络图谱；并利用多种基因敲除小鼠，探索自噬缺失对小鼠结肠组织非可控炎症及结肠肿瘤发生的影响。我们的研究将丰富现有的炎症调节理论，为改善肿瘤的治疗提供新的分子靶点和理论依据。

中文关键词： 非可控炎症；泛素化；选择性自噬；自噬降解；货物识别受体

英文摘要： Activation of nonresolving inflammation leads to continued expression of inflammatory cytokines in cells and tissues, followed with tissue damage and tumorigenesis. Recently, lots of clinical researches reveal that autophagy, a homeostatic process whereby eukaryotic cells target cellular proteins, organelles and invading microbes for degradation, plays a broad role in health and disease states, including cancer. Increasing evidence demonstrated that autophagy may be involved in the regulation of nonresolving inflammation, since many critical regulators of inflammation can be degraded through selective autophagy. However, little is known about the functions of the selective autophagy in nonresolving inflammation-mediated tumor development. The detailed molecular mechanisms about the regulation of specific inflammation regulators through selective autophagy by cargo receptors is still not clear. Our previous study also indicated that reversible ubiquitination plays an important role in the selective degradation of inflammatory regulators through autophagy, and identified several E3 ligases and deubiquitinases, including TRIM11 and USP19, which play critical roles in the crosstalk between inflammation and autophagy. In this project, we will combine the methods of immunology, molecular biology and computational biology to identify novel functions of autophagy in the regulation of nonresolving inflammation, and investigate the detailed mechanisms about how these ubiquitin-modification enzymes regulate autophagic complexes assembly or the recognition of autophagic substrates by cargo receptors to affect inflammation at molecular, cellular and animal level. Furthermore, we will attempt to draw the blueprint of the dynamic pattern of selective autophagy-mediated activation of inflammatory signaling. By using several kinds of knockout mice, we will investigate the relationship of autophagy, nonresolving inflammation and tumorigenesis in vivo. Our research will provide important data basis as well as novel drug targets for the treatment of cancer in future.

英文关键词： nonresolving inflammation;ubiquitination;selective autophagy;autophagic degradation;cargo receptors