ANGPTL3/8复合物调控NF-kB活化和炎症的功能及机制研究

NF-kB介导的炎症与多种重大疾病密切相关。类血管生成素家族的两个成员ANGPTL3/8（简称A3/8）能以分泌型复合物形式调控脂质代谢，但其在炎症中功能不详。申请人在青年基金支持下首次发现胞内的A8通过介导IKKg降解抑制NF-kB活化（Nature Communications，2017）。并通过预研究发现过表达A3/8在胞内也能结合；且A3/8以复合物形式靶向IL-1RAcP调控IL-1b而非TNFa介导的NF-kB活化。申请人据此推测“A3/8能以单独或结合形式，差异调控不同的NF-kB活化途径”。鉴于TLRs介导病原体诱发的炎症反应且与IL-1RAcP结构类似，故申请人将在细胞及动物水平研究A3/8复合物①在IL-1RI/TLRs通路的形成特征及调控功能；②对IL-1RAcP等靶标的调控机制；③对Il-1b及TLRs配体诱导的败血症的影响，以期丰富代谢与炎症通路的分子交谈机制。

NF-kB-mediated inflammation is greatly associated with many major human diseases. ANGPTL3 and 8, two members of the Angiopoietin-like protein family, are known to be involved in the regulation of lipid metabolism in the form of secreted protein complex. However, it is not clear whether such ANGPTL3/8 complex play any roles in the regulation of inflammation. Previously, supported by Youth Scientific Fund of NSFC, the applicant reported for the first time that the intracellular ANGPTL8 inhibited NF-kB activation by mediating the selective autophagic degradation of IKKg (Nature Communications, 2017). Furthermore, our pilot study demonstrated that, similar to the secreted form, the overexpressed intracellular ANGPTL3 and 8 interact with each other. Besides, ANGPTL3/8 regulated IL-1b- but not TNFa- induced NF-kB activation by targeting IL-1RAcP. The applicant thus deduced that “ANGPTL3 and 8 could regulate different molecular targets under various inflammatory stimulations, either in the complex or individual protein form”. Toll like receptors (TLRs), whose structures are similar to Interleukin 1 receptor accessory protein(IL-1RAcP), are vital receptors that mediate many pathogen associated molecular patterns (PAMPs)-induced NF-kB activation and inflammation. Therefore, by using studies at the cellular and animal levels, the applicant proposes to further investigate 1）the formation and function(s) of ANGPTL3/8 complex in the IL-1RI/TLRs signaling; 2）the mechanisms of ANGPTL3/8 in the regulation of molecular targets such as IL-1RAcP; 3）the physiological effects of Angptl3/8 in the IL-1b/TLRs ligands-induced sepsis. This study will provide new insights in the mechanisms of the crosstalk between inflammatory and metabolic signal pathways.