Institut für Medizinische Mikrobiologie

Projekttitel: "Establishment of a chronic back pain mouse model as basis for translational studies on T cell dynamics in multimodal pain therapy"

Projektdauer: 01.03.2026 - 28.02.2027

Abstract: Chronic back pain (CBP) is one of the leading causes of disability worldwide and poses a growing socio-economic burden. While multimodal pain therapy—combining pharmacological, psychological, and physical interventions—is the recommended treatment standard, the underlying immunological mechanisms re-main poorly understood. Recent evidence suggests that T cells play a critical role in the development and persistence of chronic pain, but how different components of multimodal therapy modulate T cell phenotypes is still unclear.

Emerging data suggest that amitriptyline, a commonly prescribed antidepressant in CBP, exerts immuno-modulatory effects by inhibiting acid sphingomyelinase (ASM), a key enzyme in sphingolipid metabolism. Sphingolipids influence T cell function and trafficking, highlighting a potential link between pharmacological therapy and immune modulation. Our preliminary findings indicate that amitriptyline shifts T cells toward an anti-inflammatory phenotype, increasing regulatory T cells (Tregs) and IL-10 while suppressing IFN-γ pro-duction in vitro, in vivo, and in CBP patients.

The long-term goal is to dissect the immunomodulatory effects of a multimodal pain therapy in a translational approach. To identify the underlying mechanisms of T cell contribution to chronic pain, a preclinical mouse model is indispensable. Therefore, the aim of the present proposal is to establish a mouse model for chronic back pain and to perform first analysis on T cell dynamics. These results will build the basis for a DFG grant (Sachbeihilfe) to support a PhD student conducting this immunological investigation.

Klinik für Kinderheilkunde II

Projekttitel: "Toward the First Geonme-Wide Association Study of Adrenarche: A Pilot Study"

Projektdauer: 01.03.2026 - 31.08.2027

Abstract: Adrenarche, the early rise in adrenal androgens such as DHEA, marks the first endocrine step in the transition from childhood to adolescence. It precedes gonadarche, the activation of the hypothalamic–pituitary–gonadal axis that produces gonadal sex steroids and drives the visible changes of puberty. While gonadarche has been extensively characterized through genome-wide association studies (GWAS) that identified hundreds of loci and linked pubertal timing to health outcomes, the genetic regulation of adrenarche remains unknown. A first GWAS of adrenal androgen secretion in childhood could identify novel genetic determinants and biological pathways, clarify how variation in adrenal function shapes brain development and behavior, and provide instruments for causal inference through Mendelian randomization, thereby extending modern genetic epidemiology to this critical but underexplored stage of maturation. To address this gap, we will combine two complementary cohorts. The Adolescent Brain Cognitive Development (ABCD) study is a U.S. cohort of nearly 12,000 children assessed with repeated hormone measures. The Avon Longitudinal Study of Parents and Children (ALSPAC) is a U.K. birth cohort with long-term follow-up and biobanked plasma from about 1,000 children available for LC-MS–based steroid profiling. Using ABCD as the discovery sample and ALSPAC as the replication sample, this project will conduct the first GWAS of DHEA in late childhood (9–12 years). The proposed pilot phase will harmonize genotype data and test the feasibility of LC-MS profiling in long-term stored ALSPAC samples, providing the foundation for a successful third-party grant application.

Klinik für Neurologie

Projekttitel: "Cancer-Associated Stroke: From transcriptomic profiling to mechanistic redefinition"

Projektdauer: 01.03.2026 - 28.02.2027

Abstract: Ischaemic stroke and cancer rank amongst the top leading causes of death worldwide, with 15 – 20 % of stroke patients having a cancer history. Cancer substantially increases stroke risk, while stroke causes severe disability and elevated mortality in cancer patients. Despite this critical interplay, current strategies focus primarily on highly limited stroke therapies, largely neglecting how stroke impacts cancer progression or how to optimally treat patients affected by both conditions. Here, we will apply recent advances in network medicine to redefine cancer-associated stroke as a cluster of dysfunctional, multi-target signalling modules.

Using a double transgenic mouse model of lung cancer exposed to experimental stroke, we will perform a phenotypic characterisation of the affected tissue, and conduct deep transcriptomic profiling to uncover the disrupted gene regulatory mechanisms. Integrating these findings will allow the identification of dysregulated signalling modules, laying the foundation for novel, mechanism-based therapeutic targets.

This project challenges current paradigms by offering a fundamentally new, mechanism-based framework to understand two major and often comorbid disease phenotypes, holding substantial scientific impact and translational potential.

Klinik für Psychosomatische Medizin und Psychotherapie

Projekttitel: "DeepSelf Encounter: Experimental research on the psychophysiological impact of self-deepfake exposure"

Projektdauer: 01.03.2026 - 28.02.2027

Abstract: Deepfakes are synthetic media generated via artificial intelligence intended to be perceived as real, often used to impersonate individuals with malevolent intent (defamation, pornography, identity theft, propaganda, fraud). Yet, the actual (e.g. psychophysiological) effects of deepfake exposure on individuals have not been thoroughly investigated. Especially effects of exposure to deepfake versions of oneself (here DeepSelfs) have not been studied. While deepfake-based interventions are used in mental health, (e.g., mourning or trauma exposure), potential risks and effects on the individual remain unclear. This work aims to investigate the psychophysiological impact of DeepSelf exposure and underlying mechanisms. N=54 healthy adult participants are exposed to DeepSelf-videos of three valences (positive/negative/neutral) and control videos. Psychophysiological measures of distress (e.g., skin conductance, negative emotions) are assessed during the experiment. Semi-structured interviews are conducted one week after the experiment to further explore lived-experiences of DeepSelf exposure.

To our knowledge, this is the first work to investigate potential harms of DeepSelfs, to estimate risks of deepfake-based victimization and for risk-benefit estimations for clinical applications of deepfakes. The present project is planned as preparatory work for future funding applications (DFG) with the focus on the (negative) effects and potential uses of DeepSelfs on clinical populations.

Klinik für Nuklearmedizin

Projekttitel: "Imaging Tumor Lactate Transport: Toward a PET Tracer Targeting MCT1"

Projektdauer: 01.03.2026 - 28.02.2027

Abstract: Monocarboxylate transporter 1 (MCT1) plays a central role in tumor metabolism by mediating lactate uptake and supporting metabolic cooperation between hypoxic and normoxic cancer cells. BAY-8002 is a potent and selective MCT1 inhibitor with promising preclinical activity. However, the development of 18F-labeled derivatives for PET imaging of MCT1 expression remains limited. A previously reported 18F-labeled BAY-8002 analog showed extremely low radiochemical yields and was not further evaluated. This project aims to overcome these limitations by developing an optimized 18F-labeled variant of BAY-8002 to support non-invasive imaging of MCT1 and metabolic interactions in cancer. Based on molecular modeling and the available cryo-EM structure, a minor structural modification is proposed to introduce an additional interaction with Ser371 in the MCT1 binding pocket. This change is expected to retain or improve target affinity while increasing hydrophilicity and enhancing in vivo imaging properties. To increase the likelihood of success, the synthesis is designed to yield a small library of BAY-8002 derivatives to understand structure–activity relationships and radiolabeling compatibility. Radiolabeling will be performed using a recently developed deaminative radiofluorination method relying on electron-deficient heteroanilines and pyrylium-based activation. In vitro evaluation will include binding studies in MCT1-expressing cells, blocking experiments, logD determination, and serum stability. These data will guide selection of a lead compound for in vivo studies in a planned DFG follow-up proposal and support the strategic alignment of the project within the broader institutional research landscape.

Klinik für Anatomie

Projekttitel: "Role of the N-terminal ZP2 glycoprotein in pHi regulation in sperm"

Projektdauer: 01.08.2025 - 31.07.2026

Abstract: Successful fertilization depends on the adaptation of sperm motility. Hyperactivated motility enables sperm to detach from the oviductal epithelium and break through the zona pellucida (ZP) to fuse with the oocyte. The murine ZP consists of three, that of the human of four functional glycoproteins (ZP1, ZP2, ZP3, ZP4), whereby the N-terminus of ZP2 plays an important role in the taxon-specific recognition of gametes. In a previous study, I was able to show that capacitated sperm specifically bind to the recombinant N-terminal ZP2 protein, leading to an activation of sperm, which is reflected in a motility change and the loss of a specific movement pattern (clockwise chirality) (Wiesehoefer et al., 2022). Recent unpublished results show that the recombinant murine N-terminal ZP2 protein leads to an increase in [Ca2+]i in murine sperm. These results were confirmed for human ZP2 and human sperm. The underlying signaling cascade is still unknown. In this project, I will examine whether ZP2 regulates the intracellular pH (pHi) in murine and human sperm leading indirectly to an increase in [Ca2+]i through the activation of the pH-sensitive Ca2+ channel CatSper. Membrane depolarization can also activate CatSper. Therefore, the impact of ZP2 on membrane potential regulating channels like SLO3 and ENaC will complete the work program of this application. Fluorometric pHi and membrane potential analysis of sperm treated with specific channel inhibitors before stimulation with ZP2 will be conducted. The identified signaling cascade will be verified by sperm motility analysis.

Klinik für Neurologie

Projekttitel: "Deciphering Motoneuron Degeneration in late-onset SMA: Timing, Mechanisms, and Rescue Opportunities"

Projektdauer: 01.08.2025 - 31.07.2026

Abstract: Spinal muscular atrophy (SMA) is a neuromuscular disorder caused by a deficiency of functional survival motor neuron (SMN) protein, leading to progressive motor neuron (MN) loss and muscle weakness. While SMN-enhancing therapies are effective in early-onset cases, their limited efficacy in late-onset SMA highlights the need to understand and target secondary mechanisms of degeneration. In milder SMA forms, MN loss progresses more slowly, suggesting additional pathomechanisms beyond low SMN levels and alternative rescue mechanisms. Previous studies from our group demonstrated that astrocyte dysfunction, rather than SMN deficiency, drives MN loss by glutamate toxicity, which is reversible if addressed before MN degeneration initiates. This project aims to define the time window and mechanisms of MN loss in a late-onset SMA mouse model, focusing on postnatal days P27–P37 (we see first MN loss at around P35) and a later time point with P70 and P100. Using histology, apoptosis and stress markers, dendritic analysis (MAP2 tracing, fractal analysis), and in vitro assays (axon transport, calcium imaging, ROS) will characterize the degenerative phenotype of MNs. Importantly, analysis of the SMN interactome (between the SMN and MN) will be conducted to identify molecular partners lost or altered during degeneration and assess how nusinersen treatment modifies these interactions. The results will clarify whether MN loss in mild SMA can be decoupled from SMN levels and is driven by secondary cellular and molecular changes, informing new therapeutic strategies and a better understanding for the disease mechanisms and differences between different SMA subtypes.

Klinik für Neurologie

Projekttitel: "The Nodal Resilience Connectome project: Developing better Brain-Behaviour Neuromarkers"

Projektdauer: 01.08.2025 - 31.07.2026

Abstract: Brain-based neuromarkers, often derived from the structural connectome (SC), are vital for characterizing behavior and clinical translation. However, SC-based models yield low predictive effect sizes (R2=2-5%), a limitation not solely solvable by large samples due to the static nature of SC as a constrain. To address this, we introduce the Nodal Resilience Connectome (NRC), a novel computational framework that models brain network responses to disruptions. The NRC uniquely captures nodal co-vulnerability and orthogonality under network stress, offering a structure of network resilience, information absent in standard SCs. Our preliminary results are very promising, warranting further investigation into this approach.

Klinik für Dermatologie

Projekttitel: "Metabolic Fingerprinting of Melanoma Using Novel and Conventional PET Tracers"

Projektdauer: 01.08.2025 - 31.07.2026

Abstract: Melanoma is an aggressive form of skin cancer that often develops resistance to available therapies. Despite recent advances in treatment, a considerable number of patients continue to experience diseaseprogression and relapse. The early and precise detection of aggressive or therapy-resistant melanoma remains a major clinical challenge. This project explores innovative imaging strategies with the goal to improving the detecting and monitoring of melanoma. The utilization of PET tracers that target specific metabolic pathways, including but not limited to glucose, glutamine, and lactate metabolism, is a methodology employed in this study with the objective of visualising unique features of tumours that are often overlooked by conventional methods.

In collaboration with the Department of Nuclear Medicine (Prof. Dr. Ken Herrmann), the present study will test these tracers in experimental melanoma models and correlate imaging results with tumor biology. The ultimate objective is to develop new tools for the more accurate and earlier identification of treatment-resistant melanoma, which will ultimately contribute to more personalised and effective care. This work will also lay the foundation for future clinical applications and funding proposals in the field of oncology and nuclear medicine.

Institut für Medizinische Mikrobiologie

Projekttitel: "Gut Immunity in Colorectal Cancer: The Impact of Dietary Tryptophan"

Projektdauer: 01.08.2025 - 31.07.2026

Abstract: Colorectal cancer (CRC) develops within a complex environment shaped by what we eat, the microbes in our gut, and how our immune system responds. Among the immune cells involved, regulatory T cells (Tregs) are central to immune suppression, often allowing tumors to evade immune control. Our previous work identified GPR15, a receptor guiding Tregs to the gut, as a contributor to CRC progression. However, how GPR15 is regulated and how Treg migration can be targeted in this context remain unclear. This project explores how dietary tryptophan, a nutritional amino acid, shapes immune responses in CRC. Tryptophan is metabolized by host and microbial enzymes into bioactive compounds that activate the aryl hydrocarbon receptor (AHR), a transcription factor involved in immune regulation and known to influence GPR15 ex-pression. The central question is whether tryptophan-derived metabolites, via the AHR–GPR15 axis, control Treg migration into tumors. Using a mouse model of inflammation-driven CRC, we will manipulate dietary tryptophan levels and track tumor development, immune cell changes, and shifts in microbiota and metabolite profiles. These experiments are crucial to show that diet and microbial metabolism control immune suppression in CRC and is vital to support a third-party grant that dissects the molecular regulation of GPR15 and Treg trafficking, focusing on key tryptophan metabolites, metabolic enzymes, and cell-specific pathways. The ultimate goal is to identify precise metabolic and immunological targets to block Treg tumor infiltration and boost anti-tumor immunity. Integrating nutrition, microbiome, and immunology, this research will lay the groundwork for metabolite- or diet-based therapies to overcome immune evasion and improve CRC outcomes.

Klinik für Urologie

Projekttitel: "Advanced functional and pre-clinical evaluation of estrogen receptor signaling as immune-modulatory target in solid tumors"

Projektdauer: 01.08.2025 - 31.07.2026

Abstract: Gonadocorticoid signaling pathways are increasingly recognized as critical modulators of immunosuppressive tumor microenvironments (TMEs) across various cancers. Remarkably, this mechanism also appears in tumors of non-reproductive organs such as lung and bladder cancers. My preliminary work has identified a previously unknown immunomodulatory function of the estrogenreceptor (ER) in pancreatic ductal adenocarcinoma (PDAC) and has pointed to interleukin-6 (IL-6) as a potentially central mediator of these effects. Yet, the underlying immunological mechanisms are unclear.

I have therefore started to establish a patient-derived tissue-based testing platform for precise monitoring and modulation of the immunosuppressive functions of ER signaling both as standalone interventions and in combination with relevant chemo-/immunotherapeutic approaches. In combination with a non-destructive spatial profiling technique, this will allow me to rapidly generate functional proof of concept for the immunomodulatory roles of sex hormones in solid tumors and identify potential targets for personalized therapies, positioning me in a competitive position for the acquisition of a third-party funded research project. Overall, this work will define the impact of ER signaling on T cell function across PDAC and bladder cancer (BlaCa) and to preclinically validate identified effectors such as IL-6.