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(Sestrin 2)是一种抗氧化蛋白，参与细胞内活性氧(ROS)代谢。Sesn2在小鼠体内的突变失活激活了转化生长因子β(转化生长因子β)、血小板衍生生长因子BB(PDGFBB)和哺乳动物雷帕霉素靶标(MTOR)信号，并减轻了通过潜在转化生长因子-β结合蛋白4的小剪接变异体突变失活而建立的慢性阻塞性肺疾病小鼠模型的肺气肿。我们认为，在Sesn2基因缺陷小鼠肺成纤维细胞(MLF)和Sesn2基因缺陷小鼠中，导致转化生长因子-β、mTOR和PDGF1信号转导通路同时激活的ROS依赖和非ROS依赖机制的特征和区别。此外，我们打算阐明这些途径中的每一条都在记录中对缺乏esn2功能等位基因的Ltbp4S基因敲除(KO)小鼠的肺气肿表型改善的贡献。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esn2功能缺失突变是否对COPD具有保护作用。

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.