端粒相关的炎症代谢通路在肺部感染和免疫中的作用机制研究

Dysfunctional telomere is closely related with the aging process and the onset of degenerative diseases. The high incidence of lung infection and the associated severe inflammatory pathology have been evidenced among the aging population and therefore constitute one of major causes of mortality among the aged, but the underlying mechanism remains yet to be explored. Using the lung infection model of telomerase knockout mice we found that telomere dysfunction did not impair host defensive responses, but caused the excessive activation of inflammatory cells and the sustained inflammatory responses. Further study indicated that the observed immunopathology was related with mitochondrial abnormity and the hyper-activation of the inflammasome pathway that were likely caused by the dysfunctional telomeres. Based on these findings, we aim to further understand the effect of the shortened telomere on the balance of immunity and inflammation. We will, from the perspective of the mitochondria-mediated immunometabolism, explore the causative relationship between the extensive activation of inflammasomes and the dysfunctional telomeres, identify the key molecules that drive these pathologic processes, and thereby establish the intrinsic link between metabolism, immunity and inflammation. Our study will expand the range of telomere biology, deepen our understanding of the mechanism utilized by the hosts to maintain metabolic and immunological homeostasis, and may provide novel insight on the age-associated disorders.

端粒功能障碍与衰老和退行性疾病的发生密切相关，衰老个体常表现为肺部感染的高发性和严重的炎症性病理损伤，这已成为老年人重要死因之一，而目前人们对相关机制了解并不多。利用端粒酶基因敲除小鼠肺部感染模型，我们发现端粒异常并未损伤机体的抗菌免疫，但却引起炎症细胞过度活化和炎症应答持续放大，进一步研究显示这可能与端粒障碍引起的线粒体代谢异常和炎症小体通路活化有关。本项目在前期研究基础上，深入探究端粒缺陷对机体免疫-炎症平衡的影响，并从线粒体介导的免疫代谢角度出发，分析端粒障碍引起炎症小体异常活化的作用，探求其中关键性调控分子及其机制，从而在分子-细胞-整体水平上建立代谢-免疫-炎症之间的内在联系。预期成果将拓展端粒生物学内容，深化对机体免疫-代谢平衡机制的认识，并将为衰老相关疾病的防治提供新思路。

临床观察显示，老龄人群感染性肺炎的发病率和死亡率均显著增加，其潜在机制有待研究。端粒随细胞分裂而缩短，故谓之 “生命时钟”，但端粒功能障碍与感染、免疫和炎症之间的关系仍不清楚。本项目利用端粒酶基因敲除（Terc-/-）小鼠，通过建立耐药金葡菌肺部感染型，系统研究了端粒功能缺陷对肺部感染和炎症的影响，揭示了其对巨噬细胞炎症信号转导、活化和转归等产生的影响；阐明了端粒功能失调引起线粒体数量、结构和功能的影响，建立了线粒体代谢失调与NLRP3炎症小体通路过度活化之间的内在联系；发现并证实了PGC-1α/ERRa/TNFAIP3轴在调控线粒体稳态和炎症信号通路中的作用机制；通过分子-细胞-动物整体水平的研究，结合不同年龄组人群 PBMCs应答分析，明确了端粒功能障碍引起的代谢-免疫-炎症失调的细胞分子学基础。鉴于端粒缩短和功能障碍与衰老进程密切相关，该研究也为衰老相关肺部炎症性疾病的防治提供了新的思路和潜在靶标。基于本项目工作，课题组构建了独特的衰老相关肺部感染和免疫研究体系，以及药物筛选和分析平台，获得一些具有潜在应用价值的分子靶标和候选小分子药物。在影响因子大于5的Top期刊发表论文10篇，申请专利3项（已授权1项），培养研究生和青年教师7人。