Projects

Chronic inflammatory bowel diseases (IBD) are lifelong relapse remitting and currently uncurable diseases that are defined by a dysregulated mucosal immune system and a dysregulated intestinal barrier. Current therapy focuses on unspecific inhibition of immune reactions causing IBD. Signalling by the lipid sphingosine-1-phosphate occurs via five G-protein coupled receptors (S1PR1-5), which predominantly control trafficking of lymphocytes via the circulation, but may also modulate inflammation by other means. The goal of this project is to test the impact of different S1P receptors on IBD-relevant inflammatory processes using in vitro assays and IBD mouse models. This will serve to elucidate the role of the S1P system in intestinal inflammation in order to identify new therapeutic targets and options for IBD. 

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It is well known that secreted proteins play a central role in coordinating both basic biological functions as well as complex cellular programs. Alterations in the cells secretome composition have been associated with a myriad of different malignancies including the progression and modulation of infectious diseases and mast cell dysfunction during Crohn´s disease. Furthermore, it has been established that the paracrine actions of the so called “senescence associated secretory phenotype” are the major driver of chronic inflammation as well as several age-linked diseases including cancer and neurodegenerative afflictions. In this project alterations and perturbations of the cells secretory pathway in a time-resolved manner will be analyzed, that will be hopefully translated to several secretory disease models in the future. 

Homepage Protein Quality Group

Hepatocellular carcinoma, the most frequent form of liver cancer, is among the top fatal malignancies worldwide. Immunotherapy, in particular the activation of cytotoxic T-cells, has emerged as a promising liver cancer therapy. We discovered a protein that is an essential modulator of innate immunity by regulating major histocompatibility complex class-I molecule (MHC-I) presentation. The presentation of peptide-loaded MHC-I molecules on the surface of tumor cells plays a central role in the immune response to cancer, as these are recognized by cytotoxic T-cells. Thus, our aim is to develop proteolysis targeting chimeras for this protein, which are bifunctional small molecules designed to initiate protein degradation, to be used for the treatment of hepatocellular carcinoma.

Homepage Immune Signaling Group

The chronic recurrent skin disease hidradenitis suppurativa (HS) mainly affects people in the second and third decade of life and is associated with various co-morbidities as well as a severe reduction in quality of life. The inflammatory processes of HS can extend into deep dermal or subcutaneous regions and adapt abscessing, fistulizing and mutilating forms. Such deep-seated inflammation can only be treated symptomatically by surgical intervention. Currently, also therapeutic options for the moderate-to-severe form of HS are only limited.

In a prospective study of HS patients, the inflammatory pattern (inflammasome) was investigated under antibiotic therapy. Within the scope of this project, detailed pathway analyses will potentially reveal novel targets for therapeutic intervention. 

Fecal microbiota transfer (FMT) offers an effective therapeutic option for specific diseases, such as recurrent Clostridium difficile diarrhea, and is increasingly performed. The aim of this project is to investigate whether FMT influences the systemic immune response of patients. In this study, blood from patients receiving FMT before and at specific time points after FMT will be further analyzed using different measurement methods. The analyses will focus on important transcription factors, such as STAT-3. Studies in mouse models suggest that STAT-3 plays an important role in the interaction of intestinal bacteria and immune cells. In this project, the role of this particular transcription factor in various diseases associated with an altered microbiome will be investigated.

Homepage Infectiology

Immune-mediated inflammatory disorders (IMID) form a very heterogeneous group of diseases. The clinical manifestations are diverse and can affect virtually any organ system or tissue. However, disease development and progression are dependent on multiple factors and underlying molecular as well as pathophysiological mechanisms are not fully understood. Therefore, early specific diagnosis or selection of appropriate therapeutic strategies is difficult. Apparently dysregulations and/or disturbances in the immune system lead to loss of tolerance to endogenous tissue structures and thus, drive disease initiation and progression. In this project, three-dimensional patient profiles will be created by integrating clinical parameters as well as other data sets (e.g. proteome, metabolome, etc.) to further elucidate underlying disease mechanisms and to identify novel targets for therapeutical intervention. 

Homepage Translational Rheumatology

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Rheumatoid arthritis (RA) is the most common inflammatory rheumatic joint disease, which leads to the destruction of the affected joints via an immune-mediated chronic inflammatory process. The complex disease is polygenetically predisposed and develops under the influence of environmental and lifestyle factors. As part of a still incompletely understood pathogenesis, a dysregulation of immunological effector cascades occurs, which can lead to the recurrent initiation of inflammatory processes and promote their perpetuation. Current treatments aim at inhibiting the inflammatory end stage of the immune-mediated disease process, but with limited effectiveness in the absence of a potential for cure and relevant risks of side effects due to the induced general immune suppression. Therefore, the aim of this project is to develop innovative therapeutics for the treatment of RA. As a starting point, the therapeutic potential of a systemic application of recombinant MHCII/CII peptide complexes will be analyzed for its potential to reconstitute the disease-related loss of immunological self-tolerance through the induction of regulatory T cells. Target structures of this innovative approach are T cell receptors of autoreactive T cells with specificity for i.a. collagen type II. Aptamers as oligonucleotide-based selective high-affinity TCR ligands will be evaluated as alternative drug candidates.

Homepage Rheumatology

Type 2 Diabetes and Major Depressive Disorder (MDD) have a high comorbidity rate with fatal consequences, however, the underlying pathophysiological mechanisms remain unclear. Recent evidence indicates that insulin resistance (IR) and low-grade inflammation directly affects the central nervous system leading to alterations in brain dopaminergic signaling, and promoting anhedonia a core feature of depression. Despite its huge preventive and therapeutic potential, the link between IR, low-grade inflammation, and depression has not been investigated in humans yet.

To close this gap, we aim to assess whether brain reward signaling and its modulation by insulin are impaired in diabetes as well as a subgroup of MDD. Herefore, we perform an experimental intervention study applying intranasal insulin in healthy controls, patients suffering from type 2 diabetes and patients suffering from depression. All participants will undergo functional magnetic resonance imaging (fMRI) and will be fully characterized concerning depressive symptoms and immune-metabolic profile. A profound understanding of this neuro-metabolic interaction will open new avenues for personalized treatment of both Diabetes mellitus (type 2) and Major Depression. 

Homepage Neurometabolic Circuitry Group

IkappaB-Kinase epsilon (IKKe) is a non-canonical IkB kinase involved in both NF-kB and interferon type I signaling pathways and is therefore an important mediator of immune responses. Preliminary experiments have shown that this kinase is important for growth and progression of malignant melanoma and is expressed not only in tumor cells but also in tumor infiltrating T cells (TILs), suggesting that it plays an important role in the tumor microenvironment. Therefore, this project will investigate the role of IKKe in regulating the immune response in melanoma. For this purpose, the composition of immune, skin and tumor cells will be analyzed in more detail and verified in appropriate in vivo models. Furthermore, the findings will be compared with clinical samples.

Pain is triggered by mechanical, chemical or temperature stimuli and is passed on to the central nervous system via so-called nociceptors in the periphery to trigger an appropriate response and thus prevent tissue injury. After operations, during inflammatory reactions, during viral infections or in neuropathies, the affected persons also experience pain: under these circumstances, there are often changes in the peripheral and central nervous system, so that the perception of pain is altered. In inflammatory pain, for example, normal, harmless stimuli may be perceived as painful. In contrast in neuropathic pain states, pain can occur spontaneously and without prior stimulus. Another hallmark of neuropathic pain are severe sensory hypersensitivities as well as prolonged painful aftersensations to painful and non-painful stimuli. To date, there is no satisfactory therapy for this pain - which is partly due to a lack of understanding of the underlying pathological changes in the systems involved. The goal is to identify new therapeutic targets and use them to develop new potential therapeutics.

The genomes of many viruses are highly complex, and often the number of genes or open reading frames does not correlate with the expressed viral proteins. For instance, the genomes of the RNA viruses HIV-1 and SARS-CoV-2 encode for 18 and 29 proteins, respectively, despite having a lower number of genes or open reading frames. To generate all the necessary proteins for effective replication, different mechanisms have evolved that allow viruses to translate multiple proteins from a single mRNA. Upon entering the cell, HIV-1 and SARS-CoV-2 viruses utilize a mechanism called programmed ribosomal frameshift (PRF) to produce essential proteins for their replication. Hence, this mechanism represents an interesting target for the development of novel antiviral compounds and drug targets, which will be identified within the scope of this project.

Macrodomains are small protein domains found in a variety of nonstructural proteins of different RNA viruses. These macrodomains are enzymatically active and can cleave ADP-ribose from proteins. This post-translational modification plays a critical role in human stress response and immune regulation. Several non-structural proteins are found in the genome of SARS-CoV-2 – including Mac1, which specifically recognizes and removes mono-ADP-ribosylation from various effector proteins. The removal of this modification is directly related to the ability of SARS-CoV-2 to subvert the host immune response and is therefore essential for viral replication and persistence. Accordingly, inhibition of the enzymatic activity of Mac1 represents an attractive as well as innovative therapeutic strategy for COVID. The aim of this project is the identification and further optimization of lead structures from an initial high-throughput screening.

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PROTACs (proteolysis targeting chimeras) and molecular glues are novel, pharmacologically active agents that induce selective degradation of a target protein. In combination with potent ligands of tissue-specific E3 ligases, these novel molecules may also enable targeted degradation of structures in diseased tissue. In this medicinal chemistry project, novel degrader molecules will be developed. For this purpose, known and selective target protein ligands will be used first. After an initial evaluation of the degradation of the target protein, potent and cell-active degrader molecules will be developed by iterative optimization cycles.

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The development of new therapeutics is complex and requires close interdisciplinary collaboration between basic researchers from various disciplines, clinician scientists and data scientists. In the context of ongoing projects in the Innovation Center, it is often necessary to integrate and analyze multidisciplinary data sets. Fraunhofer IGD's range of services includes the extraction of new biomarkers from image data, the creation of dashboards for the visual presentation of results, and visual and interactive cohort analysis. Fraunhofer IGD also analyzes potential applications of quantum computing for the development of new therapeutics. By applying different methods or procedures of machine learning and artificial intelligence, complex questions as well as the development of novel biological agents can be addressed.

Biological degraders (BioDegs), representing a novel therapeutic modality, are based on antigen-binding biomolecules that possess specific modifications. The biological unit of these molecules enables them to recognize and bind to a specific target protein with high affinity, while specific modification structures (fusion proteins or glycopeptides) act as ligands, binding to corresponding surface receptors and initiating receptor-mediated endocytosis. The internalized complex is subsequently degraded in the lysosome. Thus, this approach shows great promise and can be utilized for the development of new biotherapeutic agents aimed at the specific degradation of pathogenic proteins.

In the conducted projects, among other methods, interleukin-6-mediated immunomodulation in disease models is investigated using various strategies for the specific recognition of pathogenic proteins (e.g., single-chain antibody fragments and nanobodies), as well as different BioDeg receptors. The objective of these projects is to gain insights into the pharmacokinetic and pharmacodynamic properties of various BioDeg molecules and employ these findings in the development of novel biotherapeutic agents.