HIP基因通过Hh信号调控T淋巴细胞功能影响吸烟介导的气道炎症反应

Cigarette smoking is the major risk factor for COPD, but smokers show considerable variation in their risk of developing airflow obstruction. COPD is partially genetically determined, interacting with host immunity. Hedgehog interacting protein (HIP), encoding by HIP gene, is the negative feedback regulator of Hh signaling pathway, which plays a major role in multiple aspects of embryonic development, cell proliferation, cell apotosis and tissu repair. Previous studies demonstrated that HIP gene expression level decreased significantly in COPD smokers compared with healthy smokers, and our previous study also showed HIP gene could influence inflammatory mediators using T lymphocyte cell model which was the key cell in airway inflammation. Since Hh signaling regulates T cells development and function, we suggest that HIP gene mediate the function of T lymphocyte in cigarette-induced airway inflammation via Hh signaling pathway. Based on previous research findings, We aim to explore the mechamism of HIP gene's role in cigarette-induced airway inflammation using knock out mice, cell model and inhibitor of Hh pathway.It is possible that an understanding of the role of HIP in COPD pathogenesis will lead to the development of new therapies.

吸烟是慢性阻塞性肺疾病（COPD）发病的环境因素，但个体对吸烟介导的气道异常炎症反应的易感性不同，遗传基因与宿主免疫的相互作用是原因之一。音猬因子相互作用蛋白(HIP)基因产物是Hh信号通路的负反馈调节子，后者参与组织器官发育、细胞凋亡、组织修复等。研究表明吸烟的COPD患者较健康吸烟者肺组织内HIP表达显著降低，且我们预实验发现HIP表达沉默可促进气道炎症关键细胞-T淋巴细胞炎症介质的释放，初步提示HIP基因可能通过调节T细胞功能对气道炎症程度产生影响。并且基于Hh信号通路与T细胞的发育及功能密切相关，我们推测在气道炎症中，HIP基因可能通过Hh信号通路来实现对T细胞功能的调控。在此基础上，我们拟利用HIP基因敲除动物、细胞模型及Hh信号阻断剂开展体内外实验，探讨HIP基因通过Hh信号来调节T细胞功能从而影响吸烟介导的气道炎症反应程度的机制，为COPD防治提供科学依据。

吸烟是慢性阻塞性肺疾病（COPD）发病的环境因素，但个体对吸烟介导的气道异常炎症反应的易感性不同，遗传基因与宿主免疫的相互作用是原因之一。音猬因子相互作用蛋白(HIP)基因产物是Hh信号通路的负反馈调节子，后者参与组织器官发育、细胞凋亡、组织修复等。前期研究初步提示HIP基因可能通过调节T细胞功能对气道炎症程度产生影响。并且基于Hh信号通路与T细胞的发育及功能密切相关，因此我们借助于国家自然科学青年基金项目“HIP基因通过Hh信号调控T淋巴细胞功能影响吸烟介导的气道炎症反应”(81500027) 课题的实施，力求明确在气道炎症中，HIP基因可能通过Hh信号通路来实现对T细胞功能的调控。 研究结果提示Hh信号通路可被烟雾异常激活，而被环靶明阻断后，肺气肿程度可减轻。并且参与气道炎症反应的各炎症因子受到了该基因和信号通路的调控。课题提示吸烟介导的炎症中，HIP基因及Hh信号通路参与了气道炎症的形成。为COPD防治提供科学依据，可能为未来气道炎症的治疗提供新靶点。