SIRT3调节巨噬细胞炎症与修复功能参与慢性鼻-鼻窦炎嗅觉障碍的机制研究

Olfactory dysfunction is the typical complication of patients with chronic rhinosinusitis (CRS). Recent studies show that by production balancing of inflammatory cytokines and epithelial growth factors, macrophage induce proper inflammation and promote epithelial self-renew of respiratory and intestine track. We found that SIRT3 deficiency lead to increased inflammatory cytokines (TNF-a) and decreased epithelial growth factors (EGF) secreted by macrophage. Histopathological analysis of clinical samples revealed decreased expression of SIRT3 and growth factor receptors (EGFR), increased activation of NF-κB and expression of inflammatory cytokine receptor (TNFR), indicating that SIRT3 may promote CRS-associated olfactory dysfunction by regulating the inflammatory cytokines and growth factors production. The program will further study the relationship of SIRT3 expression with the progression of CRS-associated olfactory dysfunction; the in vivo and in vitro function of SIRT3 by regulating inflammatory cytokines and growth factors production in macrophages with SIRT3 knockout mice and bone marrow reconsturction system; and the underlying molecular mechanisms by signal transduction screening. The program will provide novel evidence for the pahlogy and novel target for drug design of CRS-associated olfactory dysfunction.

嗅觉障碍是慢性鼻-鼻窦炎(chronic rhinosinusitis, CRS)患者的伴发症状。新近研究表明，巨噬细胞产生炎症性细胞因子和上皮生长因子的平衡、诱导适度炎症反应是消化道、呼吸道上皮更新的关键因素。申请者发现SIRT3缺陷的巨噬细胞产生炎症因子TNF-α和上皮生长因子EGF平衡破坏；临床样本分析发现CRS患者鼻黏膜组织SIRT3表达下降，NF-κB活化增强，炎症与生长因子失衡，提示SIRT3可能通过介导巨噬细胞产生炎症因子与上皮生长因子的平衡参与CRS导致嗅觉障碍。申请者拟进一步研究SIRT3的表达异常与CRS嗅觉障碍的相关性；并应用SIRT3缺陷小鼠和骨髓重建系统研究SIRT3调节巨噬细胞产生炎症因子与上皮生长因子的平衡参与CRS嗅觉障碍的体外与体内效应；通过信号通路筛选研究相关的分子机制，为CRS导致嗅觉障碍提供理论基础及药物研发靶点。

通过对疾病的临床资料进行了收集和分析，结合前期的临床资料发现，CRS（chronic rhinosinusitis, CRS）伴嗅觉障碍患者鼻腔黏膜中的Sirt3表达较嗅觉正常组显著降低，提示Sirt3可能参与CRS嗅觉障碍的发生发展过程。我们进一步使用前期构建的鼻炎-嗅觉障碍动物模型，发现Sirt3在CRS导致嗅觉障碍过程中可能起着保护鼻腔黏膜、促进修复性巨噬细胞发挥功能，并进一步应用Sirt3敲除小鼠证实了这一结果。在机制研究方面，我们通过Elisa和PCR检测小鼠血清及鼻腔黏膜中的细胞因子的表达，发现Sirt3可以促进修复型细胞因子的产生；分子机制方面，通过转录组测序后分析发现Sirt3可能通过TNF signaling pathway促进修复型巨噬细胞分化与功能；通过广靶代谢组学分析发现Sirt3可能通过Arginine and proline metabolism信号通路促进修复型巨噬细胞分化与功能。