p38 MAPK是丝裂原激活蛋白激酶家族成员之一，包括α、β、γ和δ四个亚型，且其分布具有组织特异性。目前研究表明，在老化的肝、皮肤等器官组织中磷酸化p38 MAPK水平增高；同样，我们在老化小鼠肺组织中也发现并报道了同样现象。然而，p38 MAPK在肺老化中作用尤其是亚型特异性调节机制尚不清楚。据此，本课题拟进一步比较基础状态下年轻、老年人肺上皮细胞内p38 MAPK磷酸化和蛋白表达水平，以及核转位情况；利用我们已建立的人肺上皮细胞原代培养老化模型，借助siRNA干扰和细胞转染等技术，确定参与人肺老化调节的p38 MAPK亚型，并观察其在上皮细胞增殖和衰老中作用；最后，通过干扰已鉴定出的p38 MAPK特定亚型，在小鼠整体水平上进一步验证p38 MAPK特定亚型在调节肺老化中作用。所获成果将有助于揭示p38 MAPK亚型特异性调节肺老化的分子机制，并为临床防治肺老化相关疾病提供新途径。

p38 mitogen-activated protein kinase(p38 MAPK) is a family member of the mitogen-activated protein kinases, which includes four different isoforms called .α、β、γ andδ，and their distribution is tissue-specific.Studies have shown that p38 MAPK active form, phospho-p38 MAPK in the liver, skin and other organs were signifcantly increased with senescence, and we have observed and reported the same phenomenon in the aging lung tissue of mice. However, the role of p38 MAPK in aging lung, especially its isoform-specific regulatory mechanism is unclear. Accordingly, this project intends to further compare the differences of p38 MAPK phosphorylation and protein expression levels, as well as nuclear translocation in young and elderly lung epithelial cell on basic state. Using the senescence cell model from primary human lung epithelial cell culture, combining with the siRNA interference and cell transfection techniques, involvement of p38 MAPK isoform in regulation of human lung senescence is identified, and its role in cell proliferation and senescence is investigated. Finally, lung function and structure are evaluated in mice with identified isoform interference for further validation the role of isoform-specific regulation in lung senescence. The results from this project will contribute to explore the molecular mechanism of specific involvement of p38 MAPK isoforms in the regulation of lung senescence, and develop novel approach for the prevention and treatment of senescence-associated lung diseases.