Investigating sestrin 2 (sesn2) control of TGF-beta, mTOR and PDGF signaling and its potential significance in the development of chronic obstructive pulmonary disease (COPD)

Sestrin 2 （sesn2）是一种参与细胞内活性氧（ROS）代谢的抗氧化蛋白。小鼠sesn2突变失活激活转化生长因子β (TGF-β)、血小板衍生生长因子BB （PDGFBB）和哺乳动物雷帕霉素靶蛋白（mTOR）信号，通过突变失活TGF-β潜在结合蛋白4 （Ltbp4S）小剪接变异体建立的COPD小鼠模型中肺气肿得到缓解。我们拟对sesn2缺陷小鼠肺成纤维细胞（mlf）和sesn2缺陷小鼠中导致TGF-β、mTOR和PDGF信号转导通路同时激活的ros依赖和ros独立机制进行表征和分化。此外，我们打算阐明这些途径在缺乏功能性sesn2等位基因的Ltbp4S敲除（KO）小鼠的肺气肿表型改善中的作用。最后，我们计划使用烟草烟雾诱导的小鼠肺气肿模型来确定sesn2功能突变丢失是否可以预防COPD。

Sestrin 2 (sesn2) is an antioxidant protein involved in the metabolism of intracellular reactive oxygen species (ROS). The mutational inactivation of sesn2 in mice activates transforming growth factor β (TGF-β), platelet derived growth factor BB (PDGFBB) and mammalian Target Of Rapamycin (mTOR) signaling, and alleviates pulmonary emphysema in a mouse model of COPD established by the mutational inactivation of the small splice variant of the latent TGF-β binding protein 4 (Ltbp4S). We propose to characterize and differentiate the ROS-dependent and ROSindependent mechanisms that lead to the simultaneous activation of the TGF-β, mTOR and PDGF signal transduction pathways in sesn2 deficient mouse lung fibroblasts (MLFs) and sesn2 deficient mice. Furthermore, we intend to clarify the contribution of each of these pathways in the documented improvement of the emphysema phenotype in Ltbp4S knock-out (KO) mice lacking functional sesn2 alleles. Finally, we plan to use a tobacco smoke induced murine emphysema model to determine whether the sesn2 loss of function mutation protects against COPD.