Despite numerous scientific breakthroughs, society is still facing global health challenges. Most diseases show complex symptomatic patterns that are orchestrated by overarching signaling pathways and driven by mechanisms such as inflammation, which are extremely difficult to identify and to understand. Within ENABLE, we strive to unravel and understand selected pathogenic mechanisms and signaling pathways to identify disease-relevant critical targets for therapeutic intervention. We will focus on three closely interconnected areas that impact on a broad range of diseases:
Dysregulation of cellular homeostasis drives diseases such as cancer and immunological disorders. We aim to investigate the molecular and spatial organization of the major pathways, focusing on their crosstalk and induction of cell death and inflammation. Understanding molecular host-pathogen interactions during infection is one of the most challenging aspects of searching for new therapeutic strategies to treat infections. We will focus on understanding the invasion mechanisms of bacteria and viruses into host cells and study the pathogenic effects of microbial toxins or virulence factors. Dissection of inflammatory signaling pathways is the key to identify crucial mediators and effectors of inflammatory processes in the human body. We will investigate mechanistic details of immune activation and processes underlying the inflammatory milieu in different pathologic conditions.
ENABLE is built on the already existing strong research networks and technology platforms at Goethe University Frankfurt, the MPI of Biophysics, the Georg-Speyer-Haus, the FIAS and the Fraunhofer ITMP. To approach the highly challenging scientific questions, we will implement novel technologies and tools, especially chemical probes and biologics, which can be used to interfere with cellular functions to a hitherto unknown level of specificity and therefore dissect regulatory networks with high precision.
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.
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.
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.
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.
Approximately 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.
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.
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.
Acute-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.
Our 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.
The 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.
Our 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 the positions will be available from April 1st, 2021 or later.