BZ26调控PPARγ/EF-Tu分子节点介导巨噬细胞极化而抑制代谢性炎症的机制

PPARγ是介导巨噬细胞功能性极化的重要核受体，也是治疗代谢性疾病的药物靶标。众多临床研究显示PPARγ特异性激动剂具有显著毒性，研发选择性强、副作用小的PPARγ新配体或调控子并阐明其在代谢性炎症中的药理学效应十分重要。本项目构建了新结构苯甲酰胺分子库，通过活性筛选获得了可特异性调控巨噬细胞极化的苯甲酰胺类似物BZ26，并发现BZ26可启动PPARγ/EF-Tu相互作用而影响巨噬细胞极化方向。据此，本项目将：1.运用BZ26，探讨其通过启动PPARγ/EF-Tu相互作用节点形成，而调控巨噬细胞发生极化的确切功能；2.通过研究PPARγ/EF-Tu对巨噬细胞极化的调控机制，揭示该分子节点在影响代谢性炎症中的地位，并据此进一步明确BZ26的药理学效应。本研究不仅可揭示PPARγ/EF-Tu介导巨噬细胞极化的新机制，而且可以筛选并发现具有潜在药用功能的新型PPARγ调控子。

PPARγ, an important drug target in metabolic disease, is a crucial nuclear receptor in regulating the functional polarization of macrophages. A number of clinical studies have shown that the specific agonists of PPARγ exhibit long-term adverse effects. In this study, we expect to search for new structural ligands or selective modulators of PPARγ with lesser side effects and clarify its pharmacological actions in metabolic inflammation. We have got a functional benzamide analog BZ26 which can specifically regulate M2 macrophage polarization. It was worth noting that BZ26 can mediate the interaction between PPARγ and EF-Tu in macrophages. Accordingly, the current study will perform the following research: 1) the exact function of BZ26 in mediating macrophage polarization by initiating PPARγ/EF-Tu interaction will be studied; 2) for this work, we will reveal the functional role of PPARγ/EF-Tu in the progression of metabolic inflammation and their mechanism in regulating macrophage polarization; and based on the revealing BZ26 mediating macrophage polarization via PPARγ/EF-Tu, we will further elucidate the pharmacological actions of BZ26 in metabolic inflammation. Conclusively, we are here proposing to comprehensively understand the mechanism of PPARγ/EF-Tu-mediated macrophage polarization, and provide novel structural selective modulators of PPARγ for treating metabolic inflammation.