Unraveling mechanisms driving cellular homeostasis, inflammation and infection
to EnABLE new approaches in translational medicine
Unraveling mechanisms driving cellular homeostasis, inflammation and infection
to EnABLE new approaches in translational medicine
Registration open!
ENABLE and SFB 1177 are organizing the 4th Frankfurt Conference on Quality Control in Life Processes (FCQC) which will take place from March 24th – 27th 2025 at Campus Westend of Goethe University Frankfurt.
The conference aims to accelerate our understanding of quality control pathways and their interconnectivity and to utilize this knowledge for the improved treatment of human diseases. It will feature interdisciplinary sessions that cover topics including quality control mechanisms and networks, the interplay between autophagy and ubiquitin in health and disease and emerging therapeutics utilizing the ubiquitin system.
For information about speakers and registration, please visit the conference website.
Organizers: Ivan Đikić, Maike Windbergs & Volker Dötsch
Conference managers: Julia Lau (SFB1177) & Laura Spindler (ENABLE)
FCQC@uni-frankfurt.de
The three alliances ENABLE, PROXIDRUGS and TheraNova are organizing the 1st Symposium on Advances in Therapeutic Approaches. The event will take place from December 5th - 6th at Campus Westend of Goethe University Frankfurt. The thematic focus will be on targeted protein degradation, technology advances, delivery, RNA therapeutics and common mechanisms of human diseases.
For information about speakers and registration, please visit the symposium website.
The event will also be used as the final event of the ENABLE clusterproject. All ENABLE members (group leaders, postdocs & PhD candidates) are asked to attend.
With Ivan Đikić, Stefanie Dimmeler and Gerhard Hummer, three researchers from ENABLE are recognized as 2024 Highly Cited Researchers in their fields on Clarivate's 2024 Highly Cited Researchers list.
Research papers in this area have ranked among the most cited from 2013 to 2023, as recorded by Web of Science.
For the seventh consecutive year, ENABLE speaker Ivan Đikić has been named as a Highly Cited Researcher recognizing his exceptional impact in the field. His research papers have ranked among the most cited from 2013 to 2023 in the two categories “Biology and Biochemistry” and “Molecular Biology and Genetics”, as recorded by Web of Science.
ENABLE Project Leaders Stefanie Dimmeler and Gerhard Hummer are recognized as Highly-Cited Researchers for their cross-field performance.
The Highly Cited Researchers list, published annually by Clarivate, is based on data from the Web of Science citation database. The 2024 edition comprises 6,636 researchers from a range of disciplines, including science, engineering, medicine, business, economics and social sciences with only 216 being recognized in two categories.
These researchers have been honored for their significant achievements, particularly through highly cited papers published in journals indexed in the Science Citation Index Expanded™ and the Social Sciences Citation Index™. Germany ranks fourth globally in terms of the number of recognized scientists.
The selection highlights the lasting influence of these researchers over an 11-year period (2013-2023), demonstrating their broad and lasting impact on the global research landscape.
In a study published in today’s issue of Science, a team around ENABLE speaker Ivan Đikić reveals how cells deploy ubiquitination and selective autophagy to combat the harmful effects of cryptic splicing, protecting against accumulation of misfolded proteins and preserving cellular health.
Splicing is a precisely regulated process facilitated by the spliceosome, a large protein complex composed of more than 200 proteins. Defects in this dynamic process cause diseases such as retinitis pigmentosa (RP), a genetic disorder that leads to progressive retina degeneration due to aberrant splicing in photoreceptor cells.
The team around Đikić now discovered a novel mechanistic link between the deubiquitinase USP39 and impaired RNA splicing. Using zebrafish and cellular models, they demonstrated that USP39 depletion mimics RP-like phenotypes with retinal degeneration. USP39 deficiency led to activation of cryptic 5’ splice sites, resulting in the production of aberrant protein isoforms that are prone to misfolding and aggregation. The misfolded proteins and protein aggregates disrupt cellular proteostasis and trigger cellular stress responses.
The team analyzed the repertoire of stress responses following USP39 depletion and found that cells ramped up ubiquitination and ER-phagy, a specialized form of selective autophagy targeting the endoplasmic reticulum (ER). By this, misfolded proteins can be removed and ER stress alleviated. If the proteotoxic burden cannot be successfully managed, then this leads to proteotoxic stress, prolongation of ER stress, and, ultimately, apoptotic cell death.
“To uncover the dynamic changes in the components of the spliceosome that can transform normal splicing into defective cryptic splicing, we had to apply a wide range of multidisciplinary approaches”, explained Cristian Prieto-Garcia, postdoctoral researcher and first author of the study.
“Mathematical and computational methods allowed us to monitor cryptic splicing, while molecular and biochemical studies revealed how spliced proteins generate toxic aggregates that eventually lead to cell death and cause a retinitis-like syndrome in the zebrafish model”, said Ivan Đikić, who brought the international team together that comprised members from several Goethe University departments, from the University of Stuttgart, the IMB Mainz, the two MPIs of Biophysics and for Heart and Lung Research, the EMBL in Grenoble, and from Chinese as well as Japanese Universities.
The result highlights the central role of the ubiquitin and autophagy systems in the pathology of spliceosome-associated diseases such as RP. They also suggest that enhancing protein degradation pathways could serve as a therapeutic approach to mitigate the toxic effects of cryptic splicing associated with multiple diseases. Ivan Đikić emphasized the far-reaching impact of this study: “This discovery opens up new avenues of research, and one of the most exciting is the targeting of aggressive, highly proliferative cancer cells that are dependent on high splicing rates”.
Together with a multidisciplinary, international team, ENABLE member Lina Herhaus (now at Helmholtz HZI) and ENABLE speaker Ivan Đikić found a new role for the so-far uncharacterized GTPase family Q protein (IRGQ). IRGQ acts within the autophagy-lysosome system, targeting misfolded MHC-I molecules for degradation. The team revealed that absence of IRGQ enhanced CD8+ T cell responses. Accordingly, reduced IRGQ levels in hepatocellular carcinoma patients and mouse models lead to improved survival outcomes by promoting anti-tumour immunity. This discovery highlights the potential of IRGQ as a target for future cancer therapies. This work was carried out in an international collaboration together with colleagues from Goethe University, Dana-Farber Cancer Institute, Harvard Medical School, Max Planck Institute of Biophysics and Johannes Gutenberg University Mainz and now published online in Cell.
From 28.10 to 30.10, the joint IRTG retreat of SFB 1177 and ENABLE brought together over 40 PhD candidates and postdocs for an enriching three-day experience. Participants engaged in in-depth project discussions, expanded their networks, and attended impactful workshops on Negotiation Skills, Pitching Your Science, and Gender Diversity in Biomedical Research. These sessions were designed to help early-career researchers refine essential skills for scientific communication and career advancement.
A special thanks to our workshop leaders: Gaby Schilling (KEPOS), Peter Kronenberg (Natural Science.Careers), and Freddie* Heithoff (Fairlanguage), whose expertise and guidance greatly enriched the retreat.
Click on the picture to see the membrane budding.
Until now, the involvement of intrinsic disorder in membrane shaping processes has not been fully understood. A multidisciplinary group around IBC2 Team Leader Ram Bhaskara now reports in PNAS detailed insights into how intrinsically disordered regions (IDRs) in proteins help remodel cellular structures, particularly within the membrane proteins of the endoplasmic reticulum (ER). Focusing on the ER-phagy receptor FAM134B, they explored how membrane-anchored disordered protein regions interact with membranes. Through advanced computer modeling and molecular dynamics (MD) simulations, the team found that – depending on context – these highly flexible regions exhibit different behaviors: Driven by their conformational entropy alone, they can sense and induce membrane curvature, thereby aiding in local remodeling. However, when combined with membrane-shaping elements like the Reticulon homology domain (RHD), they amplify large-scale remodeling processes by active scaffolding. This "Janus-like" behavior is sequence-encoded and shared among other proteins involved in ER-phagy. It allows IDRs to boost protein clustering and accelerate the reshaping of the ER, providing a fresh perspective on their role in regulation of membrane dynamics and shaping of cellular organelles during autophagy. The in silico predictions based on this model is validated by newly developed functional assays. The study is the result of a collaboration between the Bhaskara team and the groups of Ivan Đikić at IBC2 and Gerhard Hummer at Max Planck Institute of Biophysics.
ENABLE Speaker Ivan Đikić has been awarded a prestigious LOEWE-Spitzenprofessur at Goethe University Frankfurt. The Hessian LOEWE research program provides around € 3 M over five years and will support Ivan’s drug development projects, focusing on proximity induction as innovative mode-of-action. Throughout his career, Ivan dedicated his work to uncovering mechanisms that regulate cellular quality control. Early on, he pioneered the concept of ubiquitin as a versatile cellular signal. More recently, he focused on reprogramming the body’s natural degradation pathways — such as the ubiquitin and autophagy systems — to target harmful proteins or organelles. This opens up new therapeutic options for a variety of diseases like cancer, neurodegenerative disorders and infections, including those that were previously considered untreatable.
As the Hessian minister for science, Timon Gremmels, pointed out, Ivan’s activities play a vital role not only in shaping the strategic profile of the Frankfurt region, but also in fostering interdisciplinary collaborations on novel treatment options for diseases such as cancer. University president Enrico Schleiff emphasized the essential importance of Ivan’s projects for combatting cancer and expressed his gratitude towards the federal state of Hessen, as the funding line of LOEWE-Spitzenprofessur helps to retain international top scientists like Ivan Đikić in Frankfurt.
Within the framework of the LOEWE-Spitzenprofessur, Ivan will now develop proximity-inducing drugs which enable the targeted degradation of tumor-related proteins in the cell. The planned projects will be complementing and expanding the already ongoing activities in the Đikić group within the framework of the BMBF-funded Cluster4Future PROXIDRUGS, which was initiated and is led by Đikić.
Link to press release of HMWK: https://wissenschaft.hessen.de/presse/prof-dr-ivan-dikic-entwickelt-medikamente-zum-abbau-krankheitsrelevanter-proteine
Link to press release of Goethe University: https://aktuelles.uni-frankfurt.de/forschung/loewe-spitzenprofessur-prof-dr-ivan-dikic-entwickelt-medikamente-zum-abbau-krankheitsrelevanter-proteine/
On 20th September, it was World Children’s Day in Germany and ENABLE PI Anja Bremm took the opportunity to transfer her enthusiasm for science to young children. It was an exciting afternoon on the banks of beautiful river Mosel in Traben-Trarbach, with many very early-career scientists gaining first pipetting experience, being amazed at how little a microliter is. 3D models and fluorescent images provided an illustration of what cells look like, and craft lovers were in their element by cutting out cell organelles.
Irina Bezsonova
The PROXIDRUGS consortium was successfully evaluated by an independent jury and will be funded by the Federal Ministry of Education and Research (BMBF) as part of Clusters4Future initiative with up to €15 million over the next three years, starting in January 2025. PROXIDRUGS, one of seven initially successful clusters, is thus entering its second implementation phase. A primary aim of the Clusters4Future initiative is to accelerate the transfer of basic research into application.
The consortium continues to focus on research into the innovative drug class of proximity-inducing agents, so-called “proxidrugs”, by advancing required technologies and using these to develop new therapeutic strategies. “Proxidrugs” use the cell's own waste management system to degrade disease-relevant proteins in a highly specified manner. They have the potential to target 80 percent of disease-relevant proteins that have thus far been deemed as undruggable with traditional small molecules.
ENABLE speaker Ivan Đikić explains: “During the last three years we have made great progress advancing technologies and establishing new platforms that can be used to identify the building blocks for proxidrugs. These technology platforms will now be systematically developed further. We have also strategically expanded the PROXIDRUGS network, integrating numerous partners from the biotech and pharmaceutical sectors, who will contribute their specific expertise to transfer findings to medical application.”
PROXIDRUGS was established in 2021 as a regional network of nine partners from academia and industry. The network covers the entire value chain from basic research to clinical application. During the second implementation phase, 21 partners will work together on ten interdisciplinary projects, all of which are positioned in the pre-competitive space. “In preparation for the second implementation phase, it was our goal to integrate more small and medium-sized companies, alongside large pharmaceutical companies, which can strengthen the consortium in relevant areas such as structure elucidation, chemical synthesis, substance libraries and artificial intelligence. We are delighted that we were able to achieve this goal and attract some highly relevant partners,” explains Dr. Kerstin Koch, Head of the Cluster Office at the Goethe University Frankfurt.
During the first implementation phase, the course was set for the cluster’s longterm success: Through an official association with “House of Pharma & Healthcare”, the cluster aims to sustain its cluster management beyond the potential three implementation phases of the Clusters4Future initiative. Additionally, the innovation hub “Frankfurt Competence Center for Emerging Therapeutics” (FCET) was founded at the Goethe University. It bundles important technology platforms and makes them available to all existing cluster partners. In future, the FCET will also be able to offer services for external scientists and companies.
Today, the German Research Foundation (DFG) announced that the transregional CRC on functionalisation of the ubiquitin system against cancer (UbiQancer) will be funded with € 18 M for the next four years. The CRC/TRR is coordinated by Technical University Munich (speaker: Prof. Florian Bassermann) with Goethe University Frankfurt and Julius-Maximilians-Universität Würzburg as co-applicant universities, and Universities of Kiel and Mainz, Helmholtz Munich, and the MPI of Biochemistry in Martinsried being involved as partners.
The CRC/TRR aims to develop innovative therapeutic strategies by a better understanding of the role of protein ubiquitination in cancer. Scientists within the network wish to gain a mechanistic understanding of aberrant ubiquitin-dependent processes in specific tumour types: AML, B-cell neoplasms, non-small cell lung cancer and colorectal cancer. The CRC/TRR strives to establish a comprehensive exploratory hub for the discovery and functionalization of relevant vulnerabilities, and to seize this knowledge for the development of compounds against validated ubiquitin-related targets and the development of PROTACs (proteolysis targeting chimera) against oncoproteins that evade direct inhibition.
From Frankfurt side, IBC2 Directors Ivan Đikić and Stefan Müller have been heavily involved in conceptualizing the program. “In Frankfurt, the foundation for establishing this CRC/TRR was laid by the HMWK-funded LOEWE project Ub-Net”, explains Ivan Đikić. “The LOEWE network not only enabled us to generate relevant foundational data, but also kicked off the establishment of technological platforms which have become critical for projects within the CRC/TRR.”. Ivan Đikić represents Frankfurt together with Christian Münch, Director of the Institute of Systems Medicine, in the CRC/TRR’s steering board. Besides Đikić, Müller and Münch, ENABLE scientists Anja Bremm, Alexandra Stolz and Stefan Knapp are participating.
PhD candidates and Postdocs of the two consortia ENABLE and CRC 1177 met in Koblenz this week to present and discuss their research results on cellular homeostasis, infection, inflammation and autophagy. The scientific program was flanked by the workshops “Motherhood in science”, given by Dr. Lena Eckert – Netzwerk Motherhood and Science, and “Job entry and career path in industry” by Dr. Lisa Steinhauser, and rounded off by evening activities such as the hike to and visit of Fort Ehrenbreitstein during sunset.
IRTG members Anshu Khatri (Dötsch lab), Pascale Henning-Domres (Kern lab) and Ramya Lakshmana Iyer (Bremm lab) took over the organization of the retreat in addition to their responsibilities as PhD candidates. Many thanks for the inspiring and well organized networking event!
ENABLE researchers were exceptionally successful in the ERC Advanced Grant competition. Martin Beck (MPI of Biophysics), Ivan Đikić and Stefanie Dimmeler (both Goethe University) all won one of the prestigious grants that come along with research funding in the amount of € 2.5 million for the next five years. For Stefanie Dimmeler and Ivan Đikić it is already the third time that they receive the ERC Advanced Grant, Martin Beck has previously been awarded with both an ERC Starting and an ERC Consolidator Grant. The three projects are tackling highly relevant and challenging mechanistic questions in the biomedical space:
NPCvalve (Martin Beck): Nuclear pores enable transport of macromolecules between the cytoplasm and the nucleus. Recent findings indicate that there may be more functions beyond nucleocytoplasmic transport. In his project, Martin Beck plans to tackle the hypothesis that nuclear pores may act as self-regulating valves for flux across the nuclear envelope. The results of this research will contribute to a better understanding of how cells deal with acute mechanical stress and reveal new therapeutic options for diseases.
Neuroheart (Stefanie Dimmeler): Ageing has long been known as major risk factor for cardiovascular disease, although the mechanisms underlying age-related changes are far from being understood. Preliminary data show that senescence goes along with a reduction in cardiac innervation. In her project, Stefanie Dimmeler plans to reveal how the crosstalk between neuronal and vascular cells impact on maintaining a healthy heart.
ER-REMODEL (Ivan Đikić): As the largest intracellular membrane system, the ER covers important functions in numerous processes. To fulfill its diverse tasks, the ER is constantly adapting its shape. Within his project, Ivan Đikić will explore how ER-phagy pathways are driving the entire process of membrane remodelling. The emerging data will not only provide new insights into organelle dynamics, but will also help to understand the impact of ER and ER-phagy on neurodegenerative diseases, cancer and infections.
Besides tackling highly challenging questions in the field, all three projects are characterized by utilizing a combination of highly sophisticated technologies, generating unprecedented insights not only on the structural, molecular and cellular level, but also utilizing state-of-the-art bioinformatics and modelling. The results of all three are expected to aid the development of novel therapeutic strategies, which is the core aim of ENABLE and also in the focus of the initiative EMTHERA, which follows on ENABLE as a joint endeavor of Frankfurt and Mainz scientists for the next round of the federal excellence strategy.
From September 19th to 20th 2021, the EnABLE kick-off meeting took place, gathering more than 40 scientists in a highly interdisciplinary environment spanning from computational modelling, medicinal chemistry over to clinical infectiology and economics. Filled with impressive talks and intensive exchange, these two days marked another successful milestone in the strive of EnABLE to unravel and understand selected pathogenic mechanisms and signaling pathways to identify disease-relevant critical targets for therapeutic intervention in the areas of dysregulated celluar homeostasis, infections and inflammation.
Christian Münch, group leader at the IBC2, will receive the Otto Meyerhof Award 2021 by the German Society for Biochemistry and Molecular Biology (GBM). The award honours the outstanding research performance of young investigators under 40. The research of the Münch group focuses on the elucidation of cellular stress responses upon protein misfolding and as a consequence of disease-causing mutations and infections, building on Münch’s in-depth expertise in quantitative mass spectrometry and system biology approaches. To quantitatively measure small changes in protein translation, the group developed a new analytical method called multiplexed enhanced protein dynamics (mePROD) proteomics. This approach has helped to study the effects of mTOR inhibition and integrated stress response activation (Klann et al., Mol Cell 2020). It is broadly adaptable to very different research questions, as very successfully shown by Münch and his team after onset of the corona pandemic: Within a matter of a few weeks, they were able to determine host cell responses to SARS-CoV-2 infection (Bojkova et al., Nature 2020) providing important insights into changes imposed by the virus upon host cells. Further analyses revealed cellular pathways that are crucial for SARS-CoV-2 replication in cells (Klann et al., Mol Cell 2020) These studies pointed to new therapeutic targets that are now under clinical evaluation or approved for the treatment of COVID-19 patients.
The Otto Meyerhof Award is endowed with 5,000 Euros, funded by Boehringer Ingelheim Pharma. The prize ceremony will take place virtually on the 16th of September, with Christian Münch presenting the award lecture on „Dynamic protein synthesis changes in stress and disease”. For those wishing to attend the event, registration until the 14th of September is required: https://gbm-online.de/gbm-awards-event.html.
As announced today, Frankfurt scientists were successful in securing funding for the ENABLE cluster project which aims at identifying disease-relevant key targets and enabling innovative therapeutic strategies. For the next four years, the project will be supported with 8 M€ by the State of Hesse as part of the cluster initiative to prepare for the next round of the federal Excellence Strategy. The ENABLE research program is centered around inflammation, infection and cellular homeostasis, which are all impacting on a broad range of diseases, many of them with high unmet medical need. It relies on innovative technologies and close team work between basic and translational research.
“This generous financial support will enable us to utilize modern tools, such as chemical probes and biologics, for a new wave of translational drug discovery”, said Ivan Đikić from the Institute of Biochemistry II on Niederrad Campus, who shares the spokesperson responsibility with Maike Windbergs from the Institute of Pharmaceutical Technology at the Riedberg Campus. Windbergs added: “These tools enable us to interfere with cellular functions at a hitherto unknown level of specificity and will help us to gain a more precise insight into inflammation processes which determine the outcome of many diseases.”
The success of this integrated translational research is based on the participation of scientists from five faculties at Goethe University and partners such as the Max Planck Institute of Biophysics, the Fraunhofer Institute for Translational Medicine and Pharmacology, the Frankfurt Institute for Advanced Studies (FIAS) and the Georg Speyer Haus (GSH). The future plan for ENABLE is to compete for a Cluster of Excellence within the next round of the federal Excellence Strategy.
Max Planck Institute of Biophysics
Max-von-Laue-Straße 3
60438 Frankfurt am Main
Functional cellular modules have often been characterised in vitro. However, relatively little is known about their interplay and spatio-temporal arrangement in the context of living cells, i.e. their 'molecular sociology'. We use integrative, in situ structural biology techniques to study the structure, function and assembly of very large macromolecular complexes in their native environment. We rely on a diverse methodological repertoire, including cryo-EM, structural proteomics, biochemistry, imaging, animal model systems and computational modeling (Robinson et al., 2007; Beck and Baumeister, 2016). Our contribution to research within the ENABLE consortium aims to understand the mechanisms of nuclear envelope and nuclear pore complex quality control.
Institute of Biochemistry II
Goethe University Frankfurt
Theodor-Stern-Kai 7
60590 Frankfurt am Main
Our research group investigates the role of the ubiquitin system in selective autophagy and in cellular responses to hypoxia or oxidative stress. Protein ubiquitination has two major consequences: control of protein turnover by providing proteasomal and lysosomal targeting signals and governance of cell signalling networks by regulation of protein interactions and activities. We are particularly interested in deubiquitinases (DUBs), the enzymes that release conjugated ubiquitin from proteins and that maintain the dynamic state of the cellular ubiquitinome. Altered DUB activity is associated with a multitude of pathologies and DUBs represent promising novel structures for targeted therapy. Within ENABLE, we aim to increase our understanding of the physiological functions and control mechanisms of DUBs and how they contribute to cellular homeostasis.
Institute of Biophysical Chemistry
Goethe University Frankfurt
Max-von-Laue Straße 9
60438 Frankfurt am Main
Our laboratory focuses on structural and functional investigations of important biological macromolecules involved in different quality control systems. Projects include the characterization of the oocytes and stem cell quality control factor p63 that also plays essential roles as a master regulator of chromatin structure in epithelial stem cells. We investigate the structure of different active and inactive conformations of p63 as well as its interactions with other proteins such as kinases and E3 ligases. We further study the interaction and function of p53 isoforms as well as the properties of p53 mutants. In addition, we focus on the structural and functional characterization of proteins involved in apoptosis and autophagy, in particular interaction of E2 and E3 enzymes involved in the ERAD process and the function of members of the Atg8 protein family in autophagy and non-autophagy related functions such as ufmylation. We use a combination of several biophysical techniques including x-ray crystallography, NMR spectroscopy and ITC with biochemical assays, cell culture experiments and mouse tissue culture.
Institute for Pharmaceutical Chemistry
Goethe University Frankfurt
Max-von-Laue-Straße 9
Frankfurt am Main
Our research group is interested in using high resolution structural information for the design of selective chemical inhibitors, so called chemical probes. Chemical probes are versatile tools that can be used to study complex biological systems and also to evaluate a protein as a target for drug development. We will support ENABLE by providing bespoke chemical probe collections for signalling pathways of interest as well as developing and characterizing new chemical probes in collaboration with ENABLE scientists. Specifically, we are for instance collaborating with the Dötsch laboratory on targeting the protein kinase CK1, with the Lecaudey laboratory on chemical tools modulating Hippo signalling and with the Müller-McNicoll group on targeting kinases that regulate RNA splicing.
Institute for Molecular Biosciences
Goethe University Frankfurt
Max-von-Laue-Straße 13
Frankfurt am Main
Mueller-McNicoll@bio.uni-frankfurt.de
Institute of Biochemistry II
Goethe University Frankfurt
Theodor-Stern-Kai 7
60590 Frankfurt am Main
In the joint ENABLE project with Stefan Müller, I will investigate a) how SUMO conjugation-deconjugation networks and kinase-phosphatase systems affect the dynamics and interplay of membrane-less organelles (MLOs), including stress granules, PML nuclear bodies, nuclear speckles and paraspeckles, b) how RNA-protein interactions are affected by changes in SUMOylation and phosphorylation in response to cellular stress e.g. proteotoxic stress, splicing stress or hypoxia, and c) how these pathways can be targeted by small molecules or biologics to modulate MLO dynamics and potentially interfere with altered MLO dynamics in human disease.
Institute of Medical Virology
Goethe University Frankfurt
Paul-Ehrlich-Str. 40
60590 Frankfurt am Main
Our institute has many years of experience in establishing cell culture models for RNA viruses. One focus is the identification and characterization of new host factors that could then be used as antiviral targets. Our previous studies of changes in Caco-2 cells upon SARS-CoV-2 infection discovered a range of pathways essential for SARS-CoV-2 replication and revealed modulation of cellular PQC machineries and pathways involved in inflammation responses.
Within ENABLE, we will extend these analyses to gain a better understanding of SARS-CoV-2. The knowledge of cellular PQC machineries and identification of new host factors is critical for the discovery of new antiviral strategies. There are no specific antiviral therapies for viral diseases including other common cold corona-viruses and hepatitis E virus (HEV). HEV is in this context of special interest since it, similar to SARS-CoV-2, can infect the nervous system, frequently leading to neurological disorders, such as Guillain-Barre-syndrome. We will compare our findings to profiles of other common cold coronaviruses (e.g. OC43, 229E) and HEV infection acquired in the same manner. In addition, we will perform translatome proteomics in lung cell lines (e.g. A549) infected with SARS-CoV-2 or other common coronaviruses to investigate the similarities and differences between these viruses.
Institute of Biochemistry II
Goethe University Frankfurt
Theodor-Stern-Kai 7
60590 Frankfurt am Main
Our laboratory focuses on studying molecular mechanisms of the two major degradation pathways – the ubiquitin-proteasome system (UPS) and autophagy. Degradation of cellular components, either through the UPS or the lysosome (autophagy), is essential for maintaining cellular homeostasis. Disruption to either of the processes can lead to neurodegenerative diseases, cancer and other pathologies.
Within ENABLE, we focus on (i) a better understanding of quality control of organelle (ER, mitochondria, nuclear envelope) morphpology and functions as well as the cross-talk in molecular pathways that impact on stress conditions including inflammation and disease-based causes and we will increase our understanding why certain proteins/pathways are targeted by pathogens. (ii) We will assess the role of ER-phagy during SARS-CoV-2 infection and determine the effects of ER-phagy perturbation on SARS-CoV-2 replication. In addition, we will determine the influence of bacterial virulence factors on innate immune and inflammatory responses and evaluate unique and common pathways by which different bacteria (Legionella pneumophilia, Salmonella enterica, Acinetobacter baumanii) modulate organelle function, morphology and cellular homeostasis. (iii) We will explore the role of inflammation in intercellular and cell-matrix interactions of the tumor microenvironment.
Institute of Biochemistry II
Goethe University Frankfurt
Theodor-Stern-Kai 7
60590 Frankfurt am Main
Our laboratory focuses on understanding changes in cell homeostasis upon perturbation. How do cells respond to stress derived from protein misfolding, disease, or infection? How do these processes affect the different cellular compartments? We try to obtain holistic understanding of the resulting cellular changes by using molecular systems biology approaches with a major focus on time-resolved proteomics.
Within ENABLE, we will focus on i) the connection between protein quality control mechanisms guiding the response to protein misfolding in the cytosol, mitochondria, and the ER. Important aspects are unfolded protein responses, protein degradation, and the connection to cellular inflammation pathways. ii) Systems medicine characterization of cell host responses to infection with coronaviruses. We will investigate common features and virus-specific properties. Ultimately, we aim to span these two areas to understand the role of protein quality control mechanisms across stresses.
Institute of Pharmaceutical Technology and
Buchmann Institute for Molecular Life Sciences
Goethe University Frankfurt
Max-von-Laue-Str. 15
60438 Frankfurt am Main
Our research group strives to explore and understand complex disease patterns governing infection and inflammation in the human body with the overarching aim to develop novel therapeutic approaches for the effective treatment of inflammatory and infectious diseases. At the interface between life sciences and engineering, we combine our expertise in 3D human derived in vitro models and advanced label-free imaging technologies to dissect signalling pathways and unravel selected physiological and pathophysiological processes in human tissue. Further, we design innovative biomimetic drug delivery systems which allow for targeted application of novel actives and investigate their interaction with human cells and tissues as well as their therapeutic effect.
Within ENABLE, we will work in close collaboration with multiple other projects across different areas. We will use our expertise in cultivating physiologically-relevant in vitro models of different biological barriers in the human body to investigate inflammatory machineries in response to SARS-CoV-2 infection in the lung and the effects of bacterial infections in the human intestine (Area B ‘Infection’). We will further investigate the human intestinal epithelium in response to different pathological states (e.g. inflammatory bowel disease and systemic inflammation) to understand overarching inflammatory pathways in order to identify novel targets and to evaluate the potential of novel actives (Area C ‘Inflammation’). In order to establish a deeper understanding of cell-cell and cell-matrix interactions in the tumor microenvironment, we will design tailor-made extracellular matrices as scaffolds for the cultivation of three-dimensional cancer tissue models. The implementation of label-free confocal Raman microscopy across different projects enables us to gain novel insights into the interactions of cells with their environment as well as with novel actives in a non-invasive and yet chemically-selective imaging approach.
Institute of Cardiovascular Regeneration
Goethe University Frankfurt
Theodor-Stern-Kai 7
60590 Frankfurt am Main
In ENABLE, we plan to dissect the role of mutations leading to clonal hematopoiesis of indetermined potential (CHIP) in the inflammatory response. Mutations in the epigenetic regulators TET2 or DNMT3A but also in various other genes can lead to the expansion of hematopoietic stems and are associated with a higher incidence of cardiovascular disease. Our own recent studies further demonstrate a worsening of prognosis in CHIP mutant carrying heart failure patients or patients with aortic stenosis. I this project, we now have the following aims: 1) Characterize the impact of mutations in TET2 and DNMT3A driver genes on the transcriptome of monocytes, 2) Identify druggable targets and develop small molecules that interfere with the increased inflammatory signatures of TET2 or DNMT3A mutant carrying hematopoietic cells, and 3) Test therapeutic strategies to reduce CHIP-associated inflammatory burden.
Institute for Clinical Pharmacology
Goethe University Frankfurt and
Fraunhofer Institute for Translational Medicine and Pharmacology
Theodor-Stern-Kai 7
60590 Frankfurt am Main
Fraunhofer Institute for Translational Medicine and Pharmacology
Industriepark Hoechst, G879
65926 Frankfurt am Main
Chronic inflammation and excessive inflammatory responses to tissue injury or infection are important underlying or exacerbating factors of a broad spectrum of disorders. Forward translational approaches to understand the molecular underpinnings of inflammatory contributions to pathogenesis have often failed due to inter-species differences in the molecular components of the immune system, e.g. between rodents and humans, and results from animal models often could not be confirmed in clinical settings.
Within ENABLE, we are following an approach of reverse translation: Samples from patients with immune-inflammatory disorders or acute inflammatory responses, available through the Fraunhofer 4D Inflammation Clinic, will be analyzed using multi-omics technologies, systems biology, network analysis and machine learning to identify characteristic molecular signatures of disease, new biomarkers that predict disease trajectories, or new targets for pharmacological intervention.
Georg-Speyer-Haus and Goethe University Frankfurt
Paul-Ehrlich-Straße 42-44
60596 Frankfurt am Main
Krause@gsh.uni-frankfurt.deApproximately 40% of men and women will be diagnosed with cancer at some point during their lifetimes. Given the ageing of the population in the developed world, the incidence of cancer is expected to increase.
Therefore, this project will explore the role of inflammation in intercellular and cell-matrix interactions of the tumor microenvironment and target hypoxia- and inflammation-mediating pathways for validation and identification of novel targets in various cancers. Our goals are to a) understand cell-cell and cell-matrix interactions in the tumor microenvironment in hypoxic and inflammatory conditions, b) target hypoxia- and inflammation-mediating pathways with chemical probes or biologics and c) validate the discovered targets and identify new targets in various cancer entities. Our highly collaborative studies will include innovative technologies such as proteomics, high resolution microscopy, artificial scaffolds, computational modeling and many others to drive forward our goal of understanding cancer more completely.
Institute for Cell Biology and Neuroscience
Goethe-Universität Frankfurt
Max-von-Laue-Straße 13
60438 Frankfurt am Main
Our lab is interested in understanding how cells coordinate different biological processes including proliferation, migration, cell shape changes and cell fate acquisition to form functional organs during embryonic development. For this, we use the zebrafish embryo as an in vivo model and combine gain- and loss-of-function analyses with modern live imaging techniques. Recently, we have been focusing on the role of the Hippo signalling pathway in proliferation control and cell migration during embryonic development, and on the role of Integrin-based cell-substrate adhesion in collective migration.
Within ENABLE, we will (i) focus on the role of Hippo signalling in tissue homeostasis, in particular we will analyse cross-interactions between Hippo and the p53 family of proteins and (ii) dissect the interplay between stress granule formation and inflammation in healthy and disease state. We will combine mutants and transgenic lines analysis to high-resolution live-imaging and develop and validate small molecule inhibitors and DARPins in our in vivo model.
Department of Internal Medicine I
Goethe University Frankfurt
Theodor-Stern-Kai 7
60590 Frankfurt
christoph.welsch@kgu.deAcute-on-chronic liver failure (ACLF) is defined by organ failure in patients with acute decompensated cirrhosis and is associated with tremendously high short-term mortality. Our studies have shown that systemic inflammation, especially driven by bacterial translocation and/or inflammasomes activation, is the key mechanism inducing organ failure not only of the liver, but also in extrahepatic organs (especially kidney and brain) in ACLF. However, it remains unclear how systemic inflammation induces organ dysfunction and failure via the inflammasomes activation.
We will investigate the molecular pathways underlying the activation of liver inflammation with focus on the inflammasome that leads to the disruption of the gut barrier and, as a consequence, to systemic inflammation and organ failure of liver and kidney. Inflammasome activation in the liver and organ failure will be analysed by in vivo models of NLRP-3, ASC and Caspase-1 deficient and WT mice after induction of ACLF by lipopolysaccharides (LPS), and confirmed in human tissue.
Institute of Pharmaceutical Technology and
Buchmann Institute for Molecular Life Sciences
Goethe University Frankfurt
Max-von-Laue-Str. 15
60438 Frankfurt am Main
Our research group strives to explore and understand complex disease patterns governing infection and inflammation in the human body with the overarching aim to develop novel therapeutic approaches for the effective treatment of inflammatory and infectious diseases. At the interface between life sciences and engineering, we combine our expertise in 3D human derived in vitro models and advanced label-free imaging technologies to dissect signalling pathways and unravel selected physiological and pathophysiological processes in human tissue. Further, we design innovative biomimetic drug delivery systems which allow for targeted application of novel actives and investigate their interaction with human cells and tissues as well as their therapeutic effect.
Within ENABLE, we will work in close collaboration with multiple other projects across different areas. We will use our expertise in cultivating physiologically-relevant in vitro models of different biological barriers in the human body to investigate inflammatory machineries in response to SARS-CoV-2 infection in the lung and the effects of bacterial infections in the human intestine (Area B ‘Infection’). We will further investigate the human intestinal epithelium in response to different pathological states (e.g. inflammatory bowel disease and systemic inflammation) to understand overarching inflammatory pathways in order to identify novel targets and to evaluate the potential of novel actives (Area C ‘Inflammation’). In order to establish a deeper understanding of cell-cell and cell-matrix interactions in the tumor microenvironment, we will design tailor-made extracellular matrices as scaffolds for the cultivation of three-dimensional cancer tissue models. The implementation of label-free confocal Raman microscopy across different projects enables us to gain novel insights into the interactions of cells with their environment as well as with novel actives in a non-invasive and yet chemically-selective imaging approach.
Frankfurt Institute for Advanced Studies
Ruth-Moufang-Straße 1
60438 Frankfurt am Main
barbarossa@fias.uni-frankfurt.deOur group works at the development of analytical and computational techniques for the description of processes arising in immunology and infectious diseases. In particular, we work on (i) in-host phenomena at intracellular level (e.g. signaling pathways), or at cellular level (e.g. interactions of immune cells with infected cells or tumor cells) (ii) between-hosts dynamics (e.g. pathogen transmission and social dynamics) and on the coupling of these two scales. This allows, for example, to capture the effects of individual immunity on epidemiological outbreaks in a population, or to study molecular mechanisms and events that influence the dynamic at cellular level (e.g. cell proliferation, death, functionality). Combining elements of nonlinear and infinite-dimensional dynamics with numerical simulations and optimization, we aim at both qualitative and quantitative understanding of biological phenomena.
Within ENABLE we will work across research areas with particular focus on (i) host-pathogen interactions, which largely determine the outcome of infections and impact on the susceptibility to numerous other diseases. We will employ hybrid modeling techniques to combine models of biochemical signaling events with the macroscopic dynamics of cellular interactions and (ii) inflammation, where we aim at investigating quantitative and dynamic analysis of HIF and other inflammation-mediating signaling pathways.
House of Finance
Goethe University Frankfurt
Theodor-W.-Adorno-Platz 3
60629 Frankfurt am Main
Potentially methodologies and insights from economic research can be applied to improve on the design of clinical trials as well as treatment choices. Rainer Haselmann adds a unique aspect from the financial perspective by monitoring costs of translational research and reducing the attrition rates during the development of novel medicines. Research in financial economics has developed several empirical methodologies to provide causal impact assessment of different institutional set-ups. While these methodologies are currently applied to evaluate different regulatory frameworks in financial markets, we will adapt and extend these approaches to evaluate clinical trial set-ups and different treatment choices.
We will directly access relevant data to conduct empirical analysis. Statistical tests will be defined in close cooperation with medical scientists. These data will be used to study and evaluate incentives and/or information sharing across various actors in the supply chain of patient care. The overarching goal would be to improve patient therapy, to individualize therapy options, as well as to improve the design of clinical trials and to reduce attrition rates during the clinical development of novel medicines.
The DFG-funded Research Unit (FOR) 2774 on Foundations of Law and Finance (co-led by Haselmann) provides the needed framework and expertise from which this research will benefit.
Max Planck Institute of Biophysics
Max-von-Laue Straße 3
60438 Frankfurt am Main
gerhard.hummer@biophys.mpg.deThe Hummer group uses molecular dynamics simulations and modeling to study chemical probes in action, working hand-in-hand with the experimental teams. Artificial intelligence (AI) tools will be used to identify targets, to optimize probes and to propose intervention strategies. Critical input will come from molecular simulations of key events in selective autophagy of nuclear core complexes, ER-associated protein degradation (ERAD), and oocyte quality control. Overarching aims are to deepen the understanding of molecular events in cell homeostasis and infection and to turn this mechanistic understanding into quantitative and predictive models that lay the foundation for therapeutic strategies.
Institute of Computer Science
Goethe University Frankfurt
Robert-Mayer-Straße 11-15
60325 Frankfurt am Main
ina.koch@bioinformatik.uni-frankfurt.deOur group „Molecular Bioinformatics“ is developing and applying methods of network analysis and computational systems biology. We are applying semi-quantitative and quantitative modeling methods to explore biochemical systems. In this context, we also gain experience in data integration. We are applying graph theory and statistics to the analysis of protein-protein interaction networks for autophagy and ubiquitinated and phosphorylated proteins of Salmonella and Shigella.
We are interested in multi-scale modeling of biochemical systems based on diverse and incomplete data as it is often the case for signaling pathways. We apply Petri nets as a semi-quantitative formalism to analyze the dynamics of a system without knowing any kinetic parameter. We use stochastics and kinetic modeling techniques if the available data is sufficient.
Within ENABLE, we will build up networks of protein-protein interactions in signaling pathways upon infections with Salmonella, Shigella, and A. baumannii to identify key genes/pathways/organelles. We will design mathematical models to simulate crucial processes, to generate new hypotheses and to analyze in silico perturbation experiments, thus supporting the design of experiments during the course of the project.
The Cluster Project ENABLE - Unraveling mechanisms driving cellular homeostasis, inflammation and infection to enable new approaches in translational medicine is a newly established interdisciplinary research network which has been initiated jointly by the Goethe University Frankfurt, the Frankfurt Institute for Advanced Studies, the Fraunhofer Institute for Translational Medicine and Pharmacology, the Georg-Speyer-Haus and the Max Planck Institute of Biophysics. The network recently received funding from the State of Hesse and is looking to recruit:
