PM2.5对肺部炎症和肺癌的影响及CARD9参与其中调控的分子机制研究

Ambient particulate matter particulate matter (PM) with an aerodynamic diameter of less than 2.5 µm (PM2.5) is the most abundant pollutant in cities of China. Epidemiological studies have demonstrated that PM2.5 was associated with lung cancer incidence and mortality, consequently it was defined as Class I carcinogen by IRAC in 2013. However, the mechanism of PM2.5 carcinogenesis is still unclear..There is a common consensus that tumor generation is associated with local inflammation which can be certainly induced by PM2.5 through the immune cells such as macrophages, neutrophils and dentric cells in lung. CARD9, specially expressed in myeloid-derived immune cells, contained caspase-associated recruitment domain, can bind with Malt1 (Mucosa-associated lymphoid tissue lymphoma translocation protein 1) and Bcl10 (B-cell lymphoma/leukemia 10) to form a complex to activate IKK (IκB kinase) and NF-κB (Nuclear factor-kappa B) signal pathway which play pivotal role in inflammation. However, whether CARD9 involved the PM2.5-induced lung inflammation which may further contribute to lung cancer generation is still unknown..First, this research will focus on the effect of CARD9 on the PM2.5-induced lung inflammation by detecting inflammatory response in CARD9 knockout and wild type mice after acute or chronic exposure to PM2.5. Second, the effect of PM2.5 on lung cancer will be studied by using Kras and EGFR gene mutation mice, the tumor associated macrophages and Myeloid-derived suppressor cells will be detected after PM2.5 exposure. Furthermore, CARD9 knockout with Kras or EGFR gene mutation mice will expose to PM2.5 for 2 months, then analyze the effect of CARD9 on the lung cancer influenced by PM2.5. To further investigate the molecular mechanism of CARD9 regulation in PM2.5-induced lung inflammation and cancer influence, NF-κB and CLR (C-type lectin receptor) pathway will be detected. Taken together, we hope the relationship of CARD9, inflammation and lung cancer will be preliminarily understood by this research.

可入肺颗粒物（PM2.5）是我国首要空气污染物，对人体健康造成重要影响。PM2.5显著诱导机体肺部产生炎症，肺部免疫细胞在其中起重要作用。CARD9蛋白特异性表达于髓系免疫细胞，与Malt1、Bcl10形成复合物激活机体调控炎症的重要信号通路NF-κB，但目前CARD9在PM2.5诱导的肺部炎症中的作用并没有报道。流行病学发现PM2.5与肺癌密切相关，2013年国际癌症研究机构定义其为一类致癌物。但PM2.5影响肺癌的具体分子机制却研究很少。而肺癌的发生与炎症相关，因此研究CARD9对PM2.5诱导的肺部炎症调控进而研究其是否参与PM2.5对肺癌的影响有重要意义。.本项目中采用CARD9基因缺陷小鼠研究其在PM2.5诱导的炎症中调控作用，采用CARD9基因敲除小鼠、K-ras和EGFR基因突变的小鼠，研究PM2.5对肺癌及其微环境的影响，进而了解PM2.5影响肺癌的分子机制。