PhD Student Biochemistry - Protease Research (m/f/d)

Currently, positions are available for the following projects:
P1: Prof. Dr. Matthias Eder: Targeting of cancer-associated proteases: Novel theranostic radiopharmaceuticals for the treatment of pancreatic cancer
Based on the success story of PSMA-targeting radiopharmaceuticals for prostate cancer therapy, we will focus on identifying novel protease targets. In this project, we will focus on the identification and radionuclide targeting of PDAC-specific proteases located on pancreatic tumor or related stromal cells. Proteases are highly suitable for targeting by peptidic ligands since their molecular function is based on the selective recognition of peptidic sequence motifs. Moreover, many proteases possess exosites that further expand the drugable sequences. To ascertain strong expression of putative theranostic targets in PDAC, we will profile pre-existing mRNA based PDAC expression data followed by comprehensive proteome analyses to identify cell-surface proteases as well as components of the extracellular matrix as aberrant protease synthesis and activity is a hallmark of PDAC tumor biology. Once targets have been identified, inhibitors and cyclic peptides will be designed and characterized in existing organoid culture and in vivo models of pancreatic cancer to identify probes suitable for innovative imaging and targeted therapy approaches.

P2: Dr. Ruth Geiss-Friedlander: Investigating DPP9 regulation, substrate recognition, and non-catalytic functions
Proteolytic processing is a key regulatory mechanism in cell biology, with N-terminal sequences playing central roles in post-translational regulation. The intracellular protease DPP9 is unique in its ability to remove N-terminal dipeptides after proline (Xaa-Pro--Zaa). DPP9 has been shown to play a role in immune regulation, metabolism, and DNA repair, and its dysregulation is linked to cancer and immune disorders (reviewed in Zolg et al. 2024).
Despite its physiological importance, only a limited number of DPP9 substrates and interaction partners have been characterized. In addition to its catalytic activity, DPP9 also has non-enzymatic functions through protein interactions, highlighting the need to better understand the mechanisms regulating its activity and binding partners.
This project aims to uncover how DPP9 is regulated, identify the determinants of DPP9-substrate interactions, and define its non-catalytic functions. It offers an excellent opportunity for a motivated doctoral candidate interested in molecular cell biology, biochemistry, protein interaction networks, protease activity and regulation. For more information, visit our website.

P4: Prof. Dr. Georg Häcker: Determine the role of sub-lethal caspase-activity in primary cells
Caspases are best known for their role in apoptosis. However, although many hundreds of substrates of caspase-3 have been described, there is arguably not a single one whose role in apoptosis is in fact clearly established. We have been working on sub-lethal signaling in the apoptosis pathway and have found that caspases are active at a sub-lethal level in at least many non-apoptotic cells at homeostasis. We have identified two situations where sub-lethal substrate cleavage has physiological effects in the regulation of signal transduction. In these cases, caspase-mediated proteolysis regulates cellular signaling pathways. We have identified more substrates of at this stage uncertain significance. This project will continue with substrate identification of effector caspases in non-apoptotic cells and with the assessment of the biological role of sub-lethal caspase activity in various mammalian cell types.

P9: Prof. Dr. Thomas Reinheckel: Function and substrates of aminopeptidases during myelopoiesis.
Aminopeptidases remove one or few amino acids from the N-terminus of proteins or peptides. Although this is an apparently minor modification, it can have significant effects on the stability and function of the cleaved protein. Moreover, aminopeptidases are more and more known to function by non-catalytic interactions with other proteins. In recent years, the impressive improvements in proteomic technologies are now allowing the analysis of the complex N-terminome and the protein-protein interactome of cells and tissues. By using genetic models, we recently found that these aminopeptidases have strong impact on the differentiation of murine hematopoietic stem cells to bone marrow derived macrophages and possibly other bone marrow derived immune cells. The PhD project will explore the details of those differentiation defects, while simultaneously uncover their molecular basis with help of proteomics and single cell technologies.

We are looking for highly motivated doctoral candidates in life sciences of all nationalities who are strongly committed to basic and translational research. A Master of Science degree is required to enter the program.

Doctoral researcher (m/f/d) positions in Protease Research in Freiburg with a 3-year contract duration (Salary scheme E13 TV-L; 65 %).