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)

• Applicants: Professor Dr. Harald von Melchner, Ph.D.; Professor Dr. Norbert Weißmann
• Subject Area: Hematology, Oncology
• Term: from 2007 to 2014
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 36003005

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.

• DFG Programme: Research Grants