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Susana Andrade Institute of Biochemistry |
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Protein Structure and Function
PII proteins such as GlnK or GlnB sense the energy and the nitrogen/carbon levels of prokaryotic, archaea, and plant cells, by selectively binding ADP, Mg-ATP and 2-oxoglutarate (2-OG). The integration of these signals results in well-described conformational changes that affect the interaction of the PII protein with downstream partners. Amongst these are enzymes (e.g., glutamine synthetase, N-acetyl-L-glutamate-kinase, histidine kinase NtrB, DraG, Laspartate deaminase AspA, glucosamine 6-phosphate deaminase NagB, diguanylate cyclases/phosphodiesterase, ATase, BCCP), transcription factors (e.g., NtrC, PipX, TnrA, GlnR) and transporters (e.g., ammonium transporters, ABC transporters). In particular, canonical GlnKs specifically interact with their cognate ammonium transporter (Amt) to regulate the import of ammonium (NH4+) and prevent its toxic cytoplasmic accumulation.
Our model organism, Archaeoglobus fulgidus, contains three glnk copies, organized in distinct operons with amt genes. While GlnK1/3 and Amt1/3 are canonical regulators and transporters, GlnK2 does not recognize 2-OG, the typical PII signal for complex dissociation, and Amt2 is a transceptor. Our goal is to understand the physiological role of this new Amt2:GlnK2 pair, identify potential new downstream partner(s) and dissect the consequences of their interaction in light of the environmental ammonium levels and cellular Mg-ATP/ADP ratio.
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Sebastian Arnold Institute of Experimental and Clinical Pharmacology and Toxicology - Department II |
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Developmental Biology
Interference with functions of the transcription factor TBXT for chordoma treatment
The DNA-binding transcription factor TBXT (aka Brachyury/T) fulfills temporally restricted physiological functions for cell specification of basic tissue types during vertebrate embryogenesis (Arnold & Robertson, Nat Rev Mol Cell Biol, 2009). More recently, TBXT was identified as the main driver of rare human malignancies, so-called chordoma. Chordoma result from persisting embryonic tissues that not only express, but also rely on persisting TBXT functions as driver. Thus, TBXT is consider a prime therapeutic intervention target of chordoma, that otherwise are largely insensitive to current treatment options. Previously, we have extensively studied the physiological functions of TBXT (and related EOMES) and uncovered the molecular mode of chromatin remodelling that underlies TBXT functions as transcriptional regulator (Tosic et al. Nat Cell Biol, 2019; Schüle et al. Dev Cell, 2023; Schröder et al., Dev Cell, 2024). In the current project we will study the pathological roles of TBXT in chordoma, and delineate the roles of additional mutations in subcomponents of TBXT-associated chromatin remodelling complexes, such as the SWI/SNF (BAF) complex. The aim of this study is to define potential new avenues for therapeutic intervention of this rare, but potentially lethal condition, that to-date is largely insensitive to pharmacological treatment. The expected identification of several potential intervention targets will prospectively allow to develop highly specific strategies to inhibit TBXT functions that can be readily tested in our experimental model systems and are transferable to chordoma cell lines.
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Anne-Kathrin Classen Institute of Biology II / Hilde Mangold Haus |
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Developmental Biology
Projects in my lab focus on how tissues develop properly, grow robustly, and remain healthy. We investigate how epithelia—and, more recently, other organ systems—sense and respond to injury, inflammation, or oncogenic transformation. Leveraging the powerful genetic and experimental tools of the Drosophila system, we integrate molecular, cell, and developmental biology approaches to study these processes directly in living tissues. Our research has revealed how cells coordinate proliferation, programmed cell death, and even senescent states to drive tissue regeneration in imaginal discs, as well as how intrinsic tissue “surveillance” mechanisms detect and remove aberrant cells. We also explore how different cell populations collaborate to give rise to complex tissue architectures, focusing on processes such as germline-soma interactions during oogenesis. Through our work, we offer prospective PhD students an opportunity to engage in projects that unite cutting-edge experimental techniques with fundamental questions about how tissues are built, maintained, and protected.
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Sven Diederichs Division of Cancer Research, Department of Thoracic Surgery, University Medical Center |
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Molecular Medicine
High-throughput functional cancer genomics for targeted tumor therapy.
Cancer genome sequencing has revealed millions of different mutations in tumors - but which of these actually drive the tumorigenesis and which would mediated sensitivity or resistance to targeted therapy with small molecule inhibitors is largely unknown. Thus, our functional understanding has been largely lagging behind the now ubiquitous ability to identify sequence variants in cancer. Hence, high-throughput approaches for functional genomics are urgently needed to close this gap for our understanding of basic signaling mechanisms in cancer as well as for precision medicine treatments of cancer patients.
The Division of Cancer Research at the University Medical Center Freiburg headed by Prof. Dr. Sven Diederichs is focused on Functional Cancer Genomics and especially the high-throughput characterization of mutations in cancer genes for their impact on tumorigenesis, signaling activation and targeted therapy response (e.g. Nat Commun 2019, Nat Cell Biol 2020, Nat Commun 2024, Nat Genet 2024, Sci Adv 2025).
The method spectrum in our lab ranges from innovative techniques from molecular and cell biology like diverse CRISPR techniques (Nucleic Acids Res 2017, Hepatology 2018) or RNA-Protein complex identification (Mol Cell 2019, Nat Protoc 2020) to applications in bioinformatics and biochemistry. Our lab in Freiburg is newly equipped with state-of-the-art instrumentation.
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Bodo Grimbacher Center of Chronic Immunodeficiency, University Medical Center |
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Immunology and Virology
JAK-STAT signaling is very import for lymphocyte homeostasis. Patients with Job Syndrome/Hyper-IgE Syndrome carry dominant-negative mutations in STAT3, leading – amongst others – to the lack in Th17 cells and hence recurrent bacterial and fungal infections. For these patients, there is currently no curative therapy, as bone marrow transplantation is thought to have too many adverse side effects. This project will evaluate the possibility of gene therapy for this indication. The disease-causing mutations in STAT3 are spread all over the gene, hence replacing the mutated sequence with an expression cassette is a sensible approach. However, first attempts to do so, did not lead to the expression of the construct. Possible explanations may be the deletion of enhancer sequences when putting in the expression cassette. This, and other possibilities, need to be worked on by e.g. chromatin conformation assays. Once the expression of the corrected gene is achieved, a dominant-negative-STAT3+/- mouse model shall prove the concept of not only genetically but also functionally correcting this genetic defect. Therefore, this project will use DNA cloning technologies, DNA-editing tools, epigenetic methods, and a mouse model in order to achieve our goal to provide patients with this devastating disease a novel treatment option, and hopefully cure.
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Robert Grosse Institute for Clinical and Experimental Pharmacology and Toxicology, Department I |
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Synthetic Biology and Signalling
The thesis project aims to investigate and target nuclear actin dynamics in androgen signalling with the potential to provide novel conceptual advance for future hormone-directed therapeutic approaches in prostate cancer combining super resolution live cell imaging, biochemistry, and molecular biology. We discovered that dynamic nuclear actin assembly is crucial for transcriptional condensate formation in androgen receptor signalling. Moreover, we identified the formin DAAM2 as a novel AR co-activator driving actin polymerization directly at the AR for its activity. We thus described a novel mechanism and steroid hormone signalling concept by which nuclear actin assembly is necessary to promote transcriptional droplet formation.
To identify the interactome of steroid hormone receptors in actin-dependent condensates, we plan to conduct two different approaches with the AR in prostate cancer cells. Firstly, we will apply liquid-liquid phase separation-assisted immunoprecipitation (LAIP) to preserve and isolate the phase separation-based protein-protein interactome followed by quantitative mass spectrometry (MS) analysis. This method shall identify droplet specific interaction partners the AR. Secondly, we will perform a proximity labeling assay attaching the biotin ligase MiniTurbo to AR allowing for proximity biotinylation of its interaction partners followed by a streptavidin pulldown and MS analysis. After comparing the results of both methods, promising identified target proteins will be followed up and investigated in detail. Interaction sites will be genetically modified to investigate effects on condensate formation and transcription using established functional assays.
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Sjon Hartman Institute of Biology III / Hilde Mangold Haus |
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Molecular Plant Sciences
Epigenome editing to control transcriptional memory in plants
Epigenetic modifications allow plants to store information of prior environmental conditions, such as the well-known process of vernalization (memory of winter). In many examples, either locus-specific repressive or active histone marks are associated with reduced or enhanced transcriptional activity of the underlying gene, respectively. Causal evidence between specific marks and gene activity, on a locus specific level, is however limited. Using epigenome editing tools, such as SunTag, we aim to engineer (encode or erase) transcriptional memory of key plant development and stress genes, and test the physiological consequences.
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Tobias Hermle Department of Medicine, Renal Division, University Medical Center |
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Molecular Medicine
Our lab investigates hereditary glomerular diseases using the Drosophila and mouse models, as well as organoids. This PhD project will focus on disease-related genes, including those encoding collagen IV, which are associated with Alport syndrome—a severe and progressive kidney disease. The Alport spectrum represents the second most common genetic cause of kidney disease.
The complex cellular architecture of the glomerular filtration barrier is not reflected in immortalized cells. Instead, we use Drosophila nephrocytes, which form a molecularly conserved slit diaphragm analogous to the kidney. A humanized Drosophila model with transgenic expression of human collagens has been established to serve as a platform to characterize patient-derived DNA variants.
The project will explore the collaborative function of the slit diaphragm, particularly its main structural protein nephrin, and collagen IV as backbone of the basement membrane. Additionally, whole-animal drug screening in Drosophila will aim to discover novel therapies.
Applied techniques will include super-resolution and live cell imaging, genome editing, DNA cloning for transgenesis, tracer studies, transcriptomics, and kidney organoids. By leveraging Drosophila's genetic tractability, complemented by human organoids, this research aims to advance the understanding of glomerular (patho)biology and inform future therapies. This project is ideal for candidates interested in basic research firmly linked to clinical nephrology.
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Bernd Kammerer Hilde Mangold Haus |
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Molecular Medicine
Metabolomics in Biomarker Discovery for Cancer
Metabolomics, the comprehensive analysis of small-molecule metabolites within biological systems, has emerged as a powerful tool in biomarker discovery for cancer. By capturing metabolic alterations associated with tumor progression, metabolomics provides valuable insights into disease mechanisms, early detection, treatment responses and contributing to advancements in precision oncology.
Cancer cells exhibit distinctive metabolic reprogramming, such as enhanced glycolysis (Warburg effect) and altered lipid metabolism, making metabolites promising biomarkers. Metabolomics enables the identification of these metabolic signatures, aiding in non-invasive diagnostics and personalized treatment strategies.
In our Metabolomics group analytical techniques, including mass spectrometry (MS) and nuclear magnetic resonance (NMR) spectroscopy, facilitate high-throughput metabolite profiling from biofluids (e.g., blood, urine) and tissues. Data-driven approaches, integrating machine learning and multi-omics strategies, enhance biomarker specificity and robustness.
Metabolomics holds immense potential for transforming cancer biomarker discovery.
By enabling early diagnosis, monitoring therapeutic efficacy, and uncovering novel drug targets, it paves the way for precision oncology. Future research should focus on standardization, validation in clinical settings, and integration with other omics technologies to maximize translational impact.
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Jürgen Kleine-Vehn Institute of Biology II, Dept. of Molecular Plant Physiology |
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Molecular Plant Sciences
The Kleine-Vehn group investigates the molecular and cellular mechanisms that govern plant growth and development. In the presumptive thesis work, we will focus on the interplay of diverse phytohormones and their cellular effectors that coordinate growth. We aim to unravel how plants integrate environmental information into developmental programs, ultimately shaping fundamental processes such as cell division and expansion, organ patterning, and overall plant architecture. By combining advanced developmental and molecular genetics, live-cell imaging, and biochemical assays, our research dissects how signal transduction pathways converge to regulate cell and tissue-level growth, leading to physiological and stress acclimation. We focus on traits of agricultural importance, allowing us to bridge fundamental research with translational perspectives. The actual project outline would be individually defined to match the expertise and interest of the candidate.
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Thomas Reinheckel Institute for Molecular Medicine and Cell Research |
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Molecular Medicine
Aminopeptidases, enzymes that cleave amino acids from the N-terminus of proteins, significantly influence protein stability and function. Recent advances in proteomics have enabled detailed analysis of the N-terminome, revealing novel insights into their biological roles.
We previously identified Methionine-aminopeptidases (METAP1 and METAP2) as key sensitizers of breast cancer cells to PI3K pathway inhibitors1. Preliminary studies suggest METAPs influence ribosome biogenesis and cell cycle progression. Our current research focuses on METAP targets in ribosome assembly, cell cycle progression and their interplay with the PI3K/mTOR pathway, a known regulator of translation and cell cycle.
Dipeptidylpeptidases (DPP8 and DPP9) are another class of aminopeptidases of interest. They cleave dipeptides from protein N-termini, particularly after proline or alanine. DPP9 has been linked to autophagy, tamoxifen response, and tumor progression in breast cancer models2,3. DPP9 also regulates the NLRP1 inflammasome, implicating it in inflammasomopathies and inflammation-related cancer. However, the extent of functional redundancy between DPP8 and DPP9 is unclear. Our current research is underway to knockout DPP8/9 selectively, identify their substrate repertoires, and explore their roles in monocyte/macrophage differentiation and inflammation in breast cancer.
In the context of these studies we are happy to discuss and offer PhD projects that aim to elucidate aminopeptidase-driven processes in cancer and immunity.
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Eva Rog-Zielinska Institute for Experimental Cardiovascular Medicine |
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Molecular Medicine
Single organelle dynamics in cardiac myocytes
Cardiac muscle cell organelles are dynamic structures, and are affected by the motion of the heart. We have recently demonstrated that cardiac organelle are deformed during the contraction of the heart, and that this deformation regulated the function of these organelles.
The project aims to develop approaches for simultaneous multi-organelle imaging in primary cardiac myocytes, subjected to stretch and contraction. The student will investigate both the structure (shape, position) and the function (diffusion speed, calcium dynamics) of organelles such as mitochondria, nuclei, sarcoplasmic reticulum, microtubules.
The workflow will include testing of various fluorescent organelle stains in living cells using confocal microscopy. Organelle dynamics (motility, interactions between organelles) will be analysed in time lapse images. The cells will be subjected to electrical and mechanical stimulation to investigate how cardiac activity affects single organelle dynamics. Light microscopy will be complemented by electron microscopy to investigate the nano-scale changes in organelle structure in healthy and diseased cells.
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Marc Timmers Centre for Clinical Research (ZKF), University Medical Center |
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Molecular Medicine
Distinct chromatin-regulatory complexes have been identified as cancer driver genes for different tumor types. Mutational inactivation of genes like KMT2D, KMT2C and UTX controlling histone H3 methylation pathways, in particular, is a hallmark of urothelial cancer. The epigenetic regulation of methylation states of lysine-4 and lysine-27 of histone H3 is disturbed at an early phase of bladder cancer. Our lab has been dissecting MLL4/KMT2D and MLL3/KMT2C functions in chromatin and transcriptional responses to TGF-ß signaling.
This PhD project will focus on the molecular and functional roles of these epigenetic regulators and of the ARID1A gene, which is a crucial subunit of the BAF chromatin remodeling complex and also frequently mutated at an early phase in bladder cancer, in chromatin and transcription control using cellular and patient-derived organoid models for this cancer. Besides a detailed molecular analysis of disrupting the above-mentioned epigenetic regulators, our bladder cancer model systems will be used to identify genetic interactions via CRISPR/Cas9 drop-out screens and chemical vulnerabilities via high-content automated microscopy screening of our FREpi chemical library. Both screens are geared towards epigenetic regulators, and can be applied directly to mouse models for bladder cancer for preclinical validations.
The PhD student will not only acquire experimental skills in state-of-the-art technologies like genomics, quantitative proteomics, genome-editing, high-throughput microscopy screening and in bioinformatic analyses of large genomic and microscopy datasets, but also be able to contribute to identify novel therapeutic strategies to counter bladder cancer on personalized basis, and thereby, improve the survival prospects of bladder cancer patients.
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