My laboratory is interested in the biology of sestrins and their significance for human disease. In mammalian cells sestrins are redox sensors that control several intracellular signal transduction pathways including Pdgfrβ, TGFβ and mTOR. Depletion of Sesn2 in genetic and environmental mouse models of chronic obstructive pulmonary disease (COPD) - a global epidemic of major proportions -, protects against disease development by activating PDGFRβ controlled alveolar maintenance programs. As patients with COPD overexpress Sesn2, we are exploring in collaboration with the University of Gießen Lung Center
the possibility of Sesn2 as a biomarker and potential drug target in the clinical management of COPD. We are further interested dissecting the multifaceted Sestrin/mTORC1 interaction under physiological conditions employing generic tag based proteomics. Within the framework of the DiGtoP consortium (From Disease Genes to Protein Pathways)
, we participated in creating a comprehensive resource of cell lines and mice with in situ tagged proteins that are expressed at nearly endogenous levels and are thus ideally suited for detecting biologically relevant protein/protein interactions.
Another topic relates to the discovery of drug resistance genes which are a major challenge in the clinical management of advanced human cancers. To address this problem effectively, individual drug resistance genes need to be placed into signal transduction pathways because pathways rather than single genes are responsible for a drug resistant phenotype. To achieve this, we are performing forward genetic screens for drug resistant phenotypes induced by targeted and non-targeted anti-leukemic drugs using the haploid human chronic myeloid leukemia cell line - KBM7 - and a conditional gene trap/protein tagging vector enabling both the recovery of drug toxicity mediating genes and tag-based proteomics under physiological conditions. By placing individual drug toxicity mediating genes into pathways, the rate of targeted drug discovery can be significantly improved because other genes within a pathway could also serve as targets and as biomarkers if their activity is altered in the diseased cells.
Finally, the recent development of genome editing tools capable of modifying any prespecified genomic sequence with unprecedented accuracy opened up a wide range of new possibilities in gene manipulation including targeted gene repair. In particular, CRISPR/Cas9, a prokaryotic adaptive immune system, and its swift repurposing for genome editing was widely adopted as the hitherto simplest genome editing tool. Using this approach, we are developing gene therapy protocols for inherited monogenic diseases based on in situ gene repair.