Forkhead box Q1通过NF-κB调控衰老相关炎症的分子机理研究

Senescent cells can secrete a variety of inflammatory factors, known as senescence associated secretory phenotype (SASP), which has multiple functions, such as preventing tumor formation when young, promoting tumor and senile disease progression during ageing and so on. Therefore, it has become the focus in cell senescence field recently. Research demonstrates that FOXQ1 which highly expresses in many tumor cells can promote tumor growth and metastasis, but its role in cellular senescence is obscure. Our previous studies has manifested that FOXQ1 can modulate senescence associated secretory phenotype via modulating SIRT1, but its mechanism is still unclear. We propose that FOXQ1 could regulate senescence associated secretory phenotype through transcriptional modulating SIRT1 and CARD6. Besides, SIRT1 could positively regulate senescence associated secretory phenotype through a feedback loop via deacetylating FOXQ1. Given this, we use chromatin immunoprecipitation, western blot, retroviral infection and other molecular biology technologies to investigate its role in the senescence associated secretory phenotype. Meanwhile, animal model will also be used to explore its role in inducing human fibroblast transformation, so as to confirm its role in cell senescence. This study will take FOXQ1 as a new perspective for revealing the mechanism of ageing, and so as to provide new ideas for the prevention and treatment of tumor and other senile diseases.

衰老细胞可以分泌多种炎症因子，称为衰老相关分泌表型（SASP）。由于SASP具有年轻时抑制肿瘤形成、衰老时促进肿瘤等老年病发生等多重作用，故其已成为近年衰老领域的研究热点。研究表明FOXQ1在多种肿瘤细胞中高表达，可以促进肿瘤细胞生长及转移，但其与细胞衰老的关系仍知之甚少。我们的预实验表明FOXQ1可以通过SIRT1调控SASP，但其作用机制仍不清楚。我们认为FOXQ1可在转录水平通过SIRT1及CARD6调控SASP；同时，SIRT1可以去乙酰化修饰FOXQ1反馈调控SASP。为此，我们用CHIP、western blot、逆转录病毒感染等多种分子生物学技术研究FOXQ1调节SASP的分子机制，同时借助动物模型方法研究其在促进人类正常成纤维细胞转化及肿瘤形成方面的作用，确证其可以调控细胞衰老。该研究将从FOXQ1这个新视点揭示细胞衰老分子机制，以期为肿瘤等老年病的防治提供新的思路。

衰老细胞可以分泌多种炎症因子，称为衰老相关的分泌表型（senescence-associated secretory phenotype，SASP）。SASP的作用具有两面性，其一方面可以促进细胞衰老，抑制肿瘤；另一方面，可以促进肿瘤等老年相关疾病发生。. 根据项目的计划，我们主要围绕FOXQ1调控SASP的分子机制，及其对细胞衰老及肿瘤发生进行了研究，主要研究内容和结果有：. （1）研究了FOXQ1通过SIRT1信号通路调控SASP的分子机制。我们发现，FOXQ1表达量伴随2BS成纤维细胞及小鼠衰老逐渐降低；过表达FOXQ1可以促进细胞增殖，抑制FOXQ1可以抑制细胞增殖；FOXQ1可以在mRNA及蛋白水平上调SIRT1，其可以结合在SIRT1启动子上促进SIRT1转录，进而调控NF-κB及炎症因子分泌；沉默FOXQ1可以抑制食管癌细胞增殖及在裸鼠体内的荷瘤能力。. （2）研究了FOXQ1在人脐带间充质干细胞hUC-MSCs衰老过程中的作用，过表达FOXQ1可以延缓hUC-MSCs衰老，并下调p16等衰老相关基因表达。将稳定过表达FOXQ1的hUC-MSCs细胞注入老年痴呆模型小鼠中，小鼠认知能力得到明显改善。. （3）研究了缺氧诱导因子1α在细胞自噬过程中的作用及机制。HIF-1α可以通过调控p27-E2F1信号通路调控自噬相关蛋白表达，阻断p27可以阻断HIF-1α的作用。. （4）初步探索了蛋白激酶D1在氧化应激情况下通过泛素蛋白酶体途径降解SIRT5的分子机制及其对胰岛β细胞凋亡的影响。