Immune tolerance and the prevention of autoimmune diseases essentially depend on thymic tissue homeostasis
The intricate balance of immune reactions towards invading pathogens and immune tolerance towards self is pivotal in preventing autoimmune diseases, with the thymus playing a central role in establishing and maintaining this equilibrium. The induction of central immune tolerance in the thymus involves the elimination of self-reactive T cells, a mechanism essential for averting autoimmunity. Disruption of the thymic T cell selection mechanisms can lead to the development of autoimmune diseases. In the dynamic microenvironment of the thymus, T cell migration and interactions with thymic stromal cells are critical for the selection processes that ensure self-tolerance. Thymic epithelial cells are particularly significant in this context, presenting self-antigens and inducing the negative selection of autoreactive T cells. Further, the synergistic roles of thymic fibroblasts, B cells, and dendritic cells in antigen presentation, selection and the development of regulatory T cells are pivotal in maintaining immune responses tightly regulated. In a recent review article these insights are discussed, offering a comprehensive examination of the multifaceted role of thymic tissue homeostasis in the establishment of immune tolerance and its implications in the prevention of autoimmune diseases. Additionally, the signaling pathways during thymus development are described, highlighting how genetic aberrations can disrupt thymic architecture and function, leading to autoimmune conditions. The impact of infections on immune tolerance is another critical area, with pathogens potentially triggering autoimmunity by altering thymic homeostasis. Overall, the review underscores the integral role of thymic tissue homeostasis in the prevention of autoimmune diseases, discussing insights into potential therapeutic strategies and examining putative avenues for future research on developing thymic-based therapies in treating and preventing autoimmune conditions.
Ehf and Fezf2 regulate late medullary thymic epithelial cell and thymic tuft cell development
The crucial role of thymic epithelial cells (TECs) in T cell maturation, selection, and the establishment of central immune tolerance is well-established. Central to these processes are the self-peptides presented by medullary thymic epithelial cells (mTECs), governed partly by the transcriptional regulator Aire and the transcription factor Fezf2. The intricate stages of mTEC maturation, such as post-Aire, Krt10+ mTECs, and Dclk1+ Tuft mTECs, coupled with their diverse gene expression profiles, present a significant challenge in deciphering the additional factors that contribute to transcriptional regulation in these cells. Our research aims to unravel the transcriptional regulators driving mTEC development and self-peptide expression comprehensively and genome-wide. We employed ATAC footprinting analysis as an indirect method to identify key transcription factors influencing mTEC gene expression, further substantiated by ChIP sequencing validation and analysis of conditional knock-out mice. The findings highlight Fezf2 as a pivotal regulator of the newly characterized thymic Tuft cells. Additionally, it was discovered that members of the ELF, ESE, ERF, and PEA3 subfamilies of ETS transcription factors, along with the Krüppel-like family of transcription factors, are instrumental in regulating genes crucial for advanced mTEC development and promiscuous gene expression. This newly identified role of Fezf2 in regulating late mTEC and Tuft-mTEC subsets enhances our understanding of the complex cellular landscape of thymic epithelial cells.
Published in Frontiers in Immunology, doi: 10.3389/fimmu.2023.1277365.
The SHDRA syndrome-associated gene TMEM260 encodes a protein-specific O-mannosyltransferase
Significance We demonstrate that the TMEM260 gene encodes a novel protein-specific O-mannosyltransferase that selectively glycosylates a common protein domain shared among cMET, RON, and plexin receptors. Biallelic mutations in TMEM260 underlie structural heart defects and renal anomalies syndrome (SHDRA), a severe developmental disorder associated with congenital cardiac malformations and early childhood mortality. We show that disease-causing mutations impair the TMEM260 O-mannosyltransferase function, which affects proprotein maturation and intracellular trafficking of receptor substrates and epithelial morphogenesis. Our study uncovers a third biosynthetic pathway for protein O-mannosylation in higher eukaryotes and identifies SHDRA as a new congenital disorder of glycosylation. Abstract Mutations in the TMEM260 gene cause structural heart defects and renal anomalies syndrome, but the function of the encoded protein remains unknown. We previously reported wide occurrence of O-mannose glycans on extracellular immunoglobulin, plexin, transcription factor (IPT) domains found in the hepatocyte growth factor receptor (cMET), macrophage-stimulating protein receptor (RON), and plexin receptors, and further demonstrated that two known protein O-mannosylation systems orchestrated by the POMT1/2 and transmembrane and tetratricopeptide repeat-containing proteins 1-4 gene families were not required for glycosylation of these IPT domains. Here, we report that the TMEM260 gene encodes an ER-located protein O-mannosyltransferase that selectively glycosylates IPT domains. We demonstrate that disease-causing TMEM260 mutations impair O-mannosylation of IPT domains and that TMEM260 knockout in cells results in receptor maturation defects and abnormal growth of 3D cell models. Thus, our study identifies the third protein-specific O-mannosylation pathway in mammals and demonstrates that O-mannosylation of IPT domains serves critical functions during epithelial morphogenesis. Our findings add a new glycosylation pathway and gene to a growing group of congenital disorders of glycosylation.
Nanobody inhibitors of Plexin-B1 identify allostery in plexin-semaphorin interactions and signalling
Plexin-B1 is a receptor for the cell surface semaphorin, Sema4D. This signalling system has been implicated in a variety of human diseases, including cancer, multiple sclerosis and osteoporosis. Whilst inhibitors of the Plexin-B1:Sema4D interaction have been previously reported, understanding their mechanism has been hindered by an incomplete structural view of Plexin-B1. In this study, we have raised and characterised a pair of nanobodies that are specific for mouse Plexin-B1, and which inhibit the binding of Sema4D to mouse Plexin-B1 and its biological activity. Structural studies of these nanobodies reveal that they inhibit the binding of Sema4D in an allosteric manner, binding to epitopes not previously reported. In addition, we report the first unbound structure of human Plexin-B1, which reveals that Plexin-B1 undergoes a conformational change on Sema4D binding. These changes mirror those seen upon binding of allosteric peptide modulators, which suggests a new model for understanding Plexin-B1 signalling, and provides a potential innovative route for therapeutic modulation of Plexin-B1.
Cowan R, Trokter M, Oleksy A, Fedorova M, Sawmynaden K, Worzfeld T, Offermanns S, Matthews D, Carr MD, Hall G. J Biol Chem 2023, 21:104740.
Plexin-B1 Mutation Drives Meastasis in Prostate Cancer Mouse Models
Metastatic prostate cancer is essentially incurable and is a leading cause of cancer-related morbidity and mortality in men, yet the underlying molecular mechanisms are poorly understood. Plexins are transmembrane receptors for semaphorins with divergent roles in many forms of cancer.
We show here that prostate epithelial cell–specific expression of a mutant form of Plexin-B1 (P1597L) which was identified in metastatic deposits in patients with prostate cancer, significantly increases metastasis, in particular metastasis to distant sites, in two transgenic mouse models of prostate cancer (PbCre+Ptenfl/flKrasG12Vand PbCre+Ptenfl/flp53fl/fl). In contrast, prostate epithelial cell–specific expression of wild-type (WT) Plexin-B1 in PbCre+Ptenfl/flKrasG12V mice significantly decreases metastasis, showing that a single clinically relevant Pro1597Leu amino-acid change converts Plexin-B1 from a metastasis-suppressor to a metastasis-promoter. Furthermore, PLXNB1P1597L significantly increased invasion of tumor cells into the prostate stroma, while PLXNB1WTreduced invasion, suggesting that Plexin-B1 has a role in the initial stages of metastasis. Deletion of RhoA/C or PDZRhoGEF in Ptenfl/flKrasG12VPLXNB1P1597L mice suppressed metastasis, implicating the Rho/ROCK pathway in this phenotypic switch. Germline deletion of Plexin-B1, to model anti-Plexin-B1 therapy, significantly decreased invasion and metastasis in both models.
Our results demonstrate that Plexin-B1 plays a complex yet significant role in metastasis in mouse models of prostate cancer and is a potential therapeutic target to block the lethal spread of the disease.
Significance: Few therapeutic targets have been identified specifically for preventing locally invasive/oligometastatic prostate cancer from becoming more widely disseminated. Our findings suggest Plexin-B1 signaling, particularly from the clinically relevant P1597L mutant, is such a target.
Shorning B, Trent N, Griffiths DF, Worzfeld T, Offermanns S, Smalley MJ, Williamson M. Cancer Res Commun 2023
Review Article on: The Role of Viral Infections in the Onset of Autoimmune Diseases
Autoimmune diseases (AIDs) are the consequence of a breach in immune tolerance, leading to the inability to sufficiently differentiate between self and non-self. Immune reactions that are targeted towards self-antigens can ultimately lead to the destruction of the host’s cells and the development of autoimmune diseases. Although autoimmune disorders are comparatively rare, the worldwide incidence and prevalence is increasing, and they have major adverse implications for mortality and morbidity. Genetic and environmental factors are thought to be the major factors contributing to the development of autoimmunity. Viral infections are one of the environmental triggers that can lead to autoimmunity. Current research suggests that several mechanisms, such as molecular mimicry, epitope spreading, and bystander activation, can cause viral-induced autoimmunity. In the newly published review article (Sundaresan et al. 2023) we describe the latest insights into the pathomechanisms of viral-induced autoimmune diseases and discuss recent findings on COVID-19 infections and the development of AIDs. Sundaresan, B., Shirafkan, F., Ripperger, K. and Rattay, K. (2023)
The Pharmacological Institute welcomes Sara Miguel Silva!
In March, Sara Miguel Silva started her doctorate in the laboratory of Mark Schmitt. Sara previously completed her master's thesis at the Faculty of Medicine of Lisbon, investigating the therapeutic potential of deflamin in colorectal cancer treatment. In her PhD thesis at the Pharmacological Institute, Sara will now devote herself to new tasks and investigate the colon cancer-promoting effects of western-style diet.
Sara Silva
December 2022
Dying tumour cells activate resistance mechanisms in neighbouring tumour cells
Colorectal cancer is the second most deadly cancer worldwide. Although recent advances in cancer research have led to substantial improvements in diagnostics and therapy, resistance of intestinal tumours to chemotherapy continues to be a major problem, contributing significantly to the mortality of patients with colorectal cancer. Mark Schmitt, research group leader at the Institute of Pharmacology, in a team of researchers from the Georg Speyer House in Frankfurt, the Goethe University Frankfurt, and from Japan and the US, has identified a mechanism that explains the heterogenic responses of tumour cells to chemotherapy: dying tumour cells release ATP (adenosine triphosphate) as a messenger substance, thereby activating an important intracellular survival pathway, via P2X4 purinoreceptors, in surrounding tumour cells. This signalling pathway protects the surrounding tumour cells from cell death, resulting in resistance to chemotherapy. In that way, dying tumour cells "alert" tumour cells in their environment and protect them against cell death. Preclinical studies have now shown that inhibiting this signalling mechanism increases the the efficacy of cytotoxic drugs against colorectal cancer.
Mark Schmitt receives a research grant from the World Cancer Research Fund
Mark Schmitt, group leader at the Institute of Pharmacology, has received a highly competitive research grant from the World Cancer Research Fund (WCRF). The funded research project will investigate how western-style diet increases the risk for colorectal cancer. A particular mechanistic focus will be on the link between western-style diet and alterations of the transcriptional and epigenomic landscape in intestinal tissues.
On October 13th, Ina Maria Schiessl, Assistant Professor at the Department of Biomedicine of the Aarhus University (Denmark), gave an exciting seminar on serial intravital multiphoton microscopy of the kidney to investigate mechanisms of renal injury and repair.
Ina Maria Schiessl
Ina Maria Schiessl
August 2022
The Institute of Pharmacology welcomes Marc Torres Pereiro!
In August, Marc Torres Pereiro has started as a PhD student in the group of Thomas Worzfeld. Before, Marc successfully completed his Master thesis at the Stem Cell Institute of the KU Leuven. In this thesis, he had analyzed the differentiation potential of mouse and human dental organoid cultures. In his PhD work, he will now study molecular mechanisms controlling epithelial plasticity in the kidney.
July 2022
Obituary for Prof. Dr. Karl Joachim Netter
Prof. Dr. Karl Joachim Netter was born in Kiel in 1929. He studied medicine at the Universities of Kiel and Freiburg and received his doctorate in Hamburg in 1953. After postdoctoral work with Feodor Lynen, who later won the Nobel Prize, at the Max-Planck-Institute for Cell Chemistry in Munich, at the Pharmacological Institute of the University of Hamburg and at the National Institutes of Health in Bethesda, he became group leader at the Pharmacological Institute of the University of Mainz in 1967. In 1976 he was appointed Director of the Institute of Pharmacology and Toxicology in Marburg, where his scientific interest focused mainly on drug metabolism and the cytochrome P-450 system. He held numerous important positions, e.g. as co-editor of the "Naunyn-Schmiedeberg's Archives of Pharmacology" and editor of the journal "Toxicology", as chairman of the Senate Commission of the German Research Foundation (DFG) for food safety, as President of the German Society for Experimental and Clinical Pharmacology and Toxicology (DGPT), as well as Vice Dean of the Faculty of Medicine at the University of Marburg. Even after his retirement in 1997, he remained very actively connected to the University, the Medical Faculty and the Pharmacological Institute in Marburg. Together with his wife Prof. Dr. Dr. Petra Netter, he was particularly dedicated to the promotion of young talents and, for example, established the Netter Endowment Fund under the umbrella of the von Behring-Röntgen Foundation, which supports young scientists and international scientific exchange. Prof. Dr. Karl Joachim Netter passed away on July 18th after a short, serious illness. With him, the Pharmacological Institute loses an excellent scientist, sponsor and pioneer for international scientific networking.
Prof. Dr. Karl Joachim Netter
July 2022
Discovery of a new pharmacological target for the treatment of gastric ulcers
Ulcer disease of the stomach and duodenum is a frequent clinical problem with potentially serious complications. A decisive factor in the pathogenesis of peptic ulcers is gastric acid. The secretion of gastric acid is controlled by the hormone gastrin released from gastric G cells. The group of Thomas Worzfeld now identified a signaling pathway, which inhibits gastrin expression on a transcriptional level and thereby limits gastrin release and gastric acid secretion. Moreover, the group could show that this signaling pathway is highly relevant for the pathogenesis of ulcers induced by non-steroidal anti-inflammatory drugs (NSAIDs), a main risk factor of ulcer disease. Activation of this signaling pathway alleviated peptic ulcer disease in mouse models. This study thereby unravels a new potential approach for the pharmacological treatment of gastric ulcers.
Experimental antibodies against osteoporosis and multiple sclerosis
Osteoporosis is a disease of the bone characterized by low bone mass and represents the most common cause for bone fractures among the elderly. Multiple sclerosis is a chronic inflammatory disease of the central nervous system (CNS). Both diseases are highly prevalent in humans; however, the currently available treatment options are limited. Therefore, new therapeutic approaches are urgently needed. The receptor, Plexin-B1, plays an important role in cell-cell communication in the bone and in inflammatory processes in the CNS. An international team from the Max-Planck-Institute for Heart and Lung Research in Bad Nauheim, the Institute of Pharmacology in Marburg and LifeArc in London has now generated an antibody against Plexin-B1. In preclinical mouse models of postmenopausal osteoporosis and multiple sclerosis, this antibody had beneficial effects on disease progression. This experimental work shows that antibodies against Plexin-B1 could potentially represent a new therapeutic approach against osteoporosis and multiple sclerosis.
From July 3rd to 6th, the Institute of Pharmacology went to a retreat at the Marburger Haus in the Kleinwalsertal, Austria. We had exciting days with intense discussions in wonderful surroundings.
The currently available treatment options for COVID-19 are limited. The aim of a project at the Institute of Pharmacology is therefore to identify novel therapeutic approaches against COVID-19 through pharmacological inhibition of particular cellular enzymes. The project is funded by the REACT-EU program.
February 2022
Ph.D. defense of Luping Zhou
On February 18th, Luping Zhou successfully defended her thesis on kidney repair mechanisms and received her Ph.D..
Congratulations, Luping!
Luping Zhou, Thomas Worzfeld
Dr. Luping Zhou
January 2022
The Institute of Pharmacology welcomes Ciarán McDonnell !
In January 2022 Ciarán McDonnell started his PhD in the group of Mark Schmitt. He completed his MSc at the National University of Ireland Galway, studying Cellular Manufacturing and Therapy. Here he wrote a thesis on a project for the repurposing of a COPD therapeutic to treat COVID-19 ARDS and co-authored a successful grant application to the Disruptive Technologies Innovation Fund. After this, he worked as a research student in the Royal College of Surgeons in Ireland, studying epigenetic changes in intestinal tissue and its impact on IBD and colorectal cancer. In his doctoral thesis at the Pharmacological Institute, Ciarán will investigate the impact of inflammatory signalling on intestinal cells and how this relates to tissue regeneration and oncogenesis.
The Institute of Pharmacology welcomes Paola Procopio!
In December, Paola Procopio started as a PhD student in the group of Dr. Schmitt. Paola successfully completed her Masters in Molecular and Cellular Biology and Biomedical Sciences at the University of “Tor Vergata” in Rome in October 2021. As part of her master's thesis, which she carried out at the IRCCS (Scientific Institute for Research, Hospitalization and Healthcare) in Rome, she examined the role of STAT3 signaling in the regulation of autophagy and the regeneration of muscle stem cells. In her doctoral thesis at the Pharmacological Institute, Paola will investigate the contribution of inflammatory signals to the activation of alternative intestinal stem cells during intestinal tissue regeneration.
Paola Procopio
November 2021
The Institute of Pharmacology welcomes Bhargavi Sundaresan!
In November, Bhargavi Sundaresan joined the Rattay Lab as Doctoral Student of Natural Sciences. Bhargavi Sundaresan completed her bachelor's degree in Biotechnology in India and her master's degree in Immunology and Inflammatory Diseases in Scotland. She then gained further practical experience at Queen Elizabeth University Hospital in Glasgow as a laboratory scientist. Bhargavi is particularly interested in immune cell-cell communication and a better understanding of inflammatory diseases and autoimmune responses.
November 2021
Highway to Thymus
New antigen access route to the thymus for central tolerance induction
The thymic self-repertoire for T-cell selection is composed of the endogenous antigen expression in epithelial cells, peripheral antigens through import by migratory dendritic cells (DCs) and diffusion of small blood-borne peptides. In a recent publication, a specialized mechanism was identified, that enables efficient thymic sampling of blood-borne antigenic macro-molecules that are too large to diffuse passively into the thymic parenchyma. In a collaborative effort with researchers from Harvard Medical School (Boston, USA), the Massachusetts General Hospital (Boston, USA), the Weizmann Institute of Science (Rehovot, Israel) and the University of Marburg (Kristin Rattay), we show that a discrete subset of DCs in murine and human thymi are uniquely positioned within the vascular wall of thymic microvessels where they project cellular processes into the bloodstream to capture circulating antigenic material. Hence, this newly identified transendothelial DCs represent a new mechanism by which the thymus can actively acquire blood-borne Ags to induce and maintain immunological tolerance.
The Institute of Pharmacology welcomes Fatemeh Shirafkan!
In October, Fatemeh Shirafkan joined the Rattay Lab as Doctoral Student of Natural Sciences. Fatemeh Shirafkan did her Bachelor and Master degree in Iran in Cell and Molecular Biology. Afterwards, she worked in a biomedical research laboratory gaining further laboratory experience. Fatemeh is particularly interested in biomedical and molecular biology research questions in the field of immunology and cancer research.
November 2021
Pathomorphological sequence of diabetic nephropathy
The group of Hermann-Josef Gröne and Wilhelm Kriz has defined the essential morphologic features of human diabetic nephropathy by using a large data set of a biopsy bank of nearly 1000 biopsies of diabetic nephropathy. Mesangial matrix expansion which can progress to nodular sclerosis is due to an accumulation of glomerular basement membrane produced by podocytes and endothelial cells. Angiogenesis at the vascular pole and at the circumference of Bowman’s capsule as well as in segmental glomerular scarring is a driving force for the progression of diabetic glomerulosclerosis. Tubular atrophy does occur only in those nephrons which exhibit sclerosis and is not an inherent characteristic of the tubules themselves.
Chen Jiang receives the Von Behring-Röntgen Young Talent Award 2021
For his outstanding scientific discoveries in the field of epidermal stem cell biology, Chen Jiang was awarded the Young Talent Award of the von Behring-Röntgen Foundation on October 6th, 2021.
The group of Hermann-Josef Gröne has shown that glycosphingolipids which, in conjunction with cholesterol, are the relevant lipids in lipid microdomains of the plasma membrane, are necessary for differentiation and resorptive functions of enterocytes. A deficiency of glycosphingolipids in intestinal enterocytes can significantly slow the development of intestinal adenomata and colon cancer probably by multiple mechanisms amongst which the inhibition of cytokinesis is an important aspect. In the kidney, proximal tubular epithelia resemble enterocytes as they also display a brush border and are active in resorption and secretion of metabolites. A selective lack of glycosphingolipids in proximal tubular epithelium protects against absorption of toxic metabolites and against acute renal failure caused by endogenous proteins (myoglobin) and antibiotics (aminoglycosides).
Nature Review Immunology article published: The inflammatory pathogenesis of colorectal cancer
Inflammation has powerful effects on tumor development and affects all steps of tumorigenesis, from tumor initiation, over tumor progression to metastasis. In our current article we review the different forms of inflammation in colorectal cancer and describe the mechansims through which chronic inflammation can initiate tumorigenesis and through which tumour- elicited and therapy- induced inflammation can promote colorectal cancer. We further specify how tumour cells engage and drive the plasticity of stromal cells in the tumormicroenvironment and how extrinsic factors, such as diet, the microbiota and the mycobiota, contribute to inflammation and tumorigenesis in colorectal cancer. We conclude by providing an outlook of how our understanding of the interplay between inflammatory immune responses and tumorigenesis can be used to develop new prevention and treatment strategies for colorectal cancer.
Dr. Kristin Rattay is appointed Professor at the Institute of Pharmacology
The Institute of Pharmacology is happy to have Dr. Kristin Rattay as a new professor since April 1st. Kristin Rattay received her Ph.D. from the German Cancer Research Center and the Heidelberg University in Germany where she worked on the transcriptional mechanisms regulating self-peptide expression in medullary thymic epithelial cells. During her Postdoc at the Harvard Medical School in Boston, USA, she studied the importance of venular endothelial cells and their role as gatekeeper cells regulating thymic tissue homeostasis. Her future research will focus on the cellular and molecular mechanisms of tolerance induction in the thymus, studying cell communication between T cells, thymic epithelial cells and endothelial cells, T cell migration through the stroma and the transcriptional regulation of self-peptide expression in the thymus.
March 2021
Dr. Mark Schmitt starts new research group on intestinal inflammation and cancer
The Institute of Pharmacology welcomes Dr. Mark Schmitt as a new research group leader. Mark Schmitt studied biology at the Karlsruhe Institute of Technology (KIT), Germany. During his Ph.D. in the lab of Prof. Dr. Véronique Orian-Rousseau at the Institute of Toxicology and Genetics in Karlsruhe, he analyzed the functional role of the stem cell marker CD44 as a feedback regulator for Wnt-signaling and CD44v6 as marker of metastatic cancer cells. He joined then joined the lab of Prof. Dr. Riccardo Fodde at the Erasmus Medical Center in Rotterdam, Netherlands, as a postdoctoral research fellow. There, he investigated the pro-tumorigenic effects of inflammation and diet on the intestinal stem cell niche. Afterwards, he moved to the lab of Prof. Dr. Florian Greten at the Georg-Speyer-Haus, Frankfurt, Germany, to work on intestinal cancer and examine cellular plasticity in colorectal cancer progression and therapy response. Since March 1st, he is now research group leader at the Institute of Pharmacology, where his work will focus on the role of cellular plasticity in intestinal inflammation and inflammation-associated colorectal cancer onset.
February 2021
Ph.D. defense of Chen Jiang
On February 23rd, Chen Jiang successfully defended his thesis with the title "The role of B-plexins for mechanochemical control of epidermal stem cell divisions in development and cancer". He received his Ph.D. with the best possible grade "summa cum laude".
January 2021
Elucidation of a mechanochemical mechanism to control epidermal stem cell divisions
The precise spatiotemporal control of cell proliferation is key to the morphogenesis of epithelial tissues. Epithelial cell divisions lead to tissue crowding and local changes in force distribution, which in turn suppress the rate of cell divisions. The molecular mechanisms underlying this mechanical feedback are largely unclear. Chen Jiang, PhD student at the institute, and co-workers from Helsinki (Finland), London (UK), Bethesda (USA), Göttingen (Germany), Cologne (Germany) and Bad Nauheim (Germany) have now identified a critical requirement of B-plexin transmembrane receptors in the response to crowding-induced mechanical forces during embryonic skin development. Epidermal stem cells lacking B-plexins fail to sense mechanical compression, resulting in disinhibition of cell divisions and tissue overgrowth. Our work provides evidence that the B-plexin-dependent mechanochemical feedback is also pathophysiologically relevant to limit tumor growth in basal cell carcinoma, the most common type of skin cancer. Our results uncover a central role of B-plexins in mechanosensation to couple cell density and cell division in development and disease.
Please click here for further information:
Photo: Chen Jiang
January 2021
A role for microtubule tyrosination in epithelial morphogenesis
Microtubules form part of the cytoskeleton, and are made up by polymers of tubulin. Tubulin can undergo a post-translational modification called tyrosination. This tyrosination is carried out by the enzyme, tubulin tyrosine ligase (TTL), which adds tyrosine to the carboxy terminus of detyrosinated alpha-tubulin. A research team of the University of Marburg, including Florian Hub and Thomas Worzfeld, has now discovered that the equilibrium between microtubules enriched in detyrosinated or tyrosinated tubulin plays an important role in epithelial morphogenesis.
TRPC1 modifies cation currents in hippocampal CA1 neurons
TRPC channel subunits (TRPC1-7) form receptor-operated cation channels. Whether TRPC1 can form channels on its own remains unclear, but TRPC1 can heteromultimerize with other TRPCs leading to changes in their functional properties. During her PhD work at the institute, Frauke Kepura (now Dormann) studied the effect of genetic deletion of TRPC1 on receptor-operated cation currents in hippocampal CA1 pyramidal neurons. Cation currents activated downstream of metabotropic glutamate receptors were modified such that inward currents were larger in TRPC1-/- neurons than in TRPC1+/+ neurones. The results indicate that TRPC1 has an inhibitory modulatory effect on cation currents (probably in heteromultimeric complexes with TRPC4 and TRPC5 with which it combines and which are co-expressed in these neurons) and probably does not form homomeric channels. Expression of TRPC1 reduces the tendency of these neurons to generate longer-lasting plateau potentials.
Gangliosides Modulate Insulin Secretion by Pancreatic Beta-Cells
Type 2 diabetes is an extremely prevalent metabolic disease characterized by high blood sugar levels and relative lack of insulin. The research group of Hermann-Josef Gröne has discovered that negatively charged sialic acid containing ganliosides are synthesized in pancreatic islets at high concentrations. These gangliosides GM3 and GD3 could increase glucose uptake by the glucose transporter GLUT2 in beta cells of pancreatic islets, leading to an increase in insulin secretion; the effect was pronounced under a high glucose load and hyperlipidemia, two conditions found in type 2 diabetes.
Carsten Höß receives the Young Investigator Award of the German Society of Pharmacology and Toxicology
The 86th Annual Meeting of the German Society for Experimental and Clinical Pharmacology and Toxicology (DGPT) was held from March 2nd to 5th in Leipzig, Germany. Carsten Höß, PhD student at the institute, gave a superb talk on his newly discovered mechanism of plexin signal transduction, and was awarded the "Young Investigator Award" of the Society.
Congratulations, Carsten!
December 2019
Christmas Party
On December 17th, we had the Christmas Party of the Biochemical-Pharmacological Center. All institutes of the Center, i.e. the Institute of Pharmacology and the Institute of Physiological Chemistry of the Medical Faculty and the Institute of Pharmacology and Clinical Pharmacy of the Pharmacy Faculty, enjoyed a wonderful relaxed evening together, with great food and drinks, nice conversations, playing games together and dancing in the disco area!
Photo: Thomas Worzfeld
November 2019
New Research Training Group „The inflammatory tumor secretome – from understanding to novel therapies”
The German Research Foundation has approved 3.9 Million Euro of funding for the years 2020 to 2024 for a Research Training Group in Marburg and Giessen in the field of cancer research. This graduate school will focus on the role of the inflammation-driven tumor secretome for tumor progression and therapy resistance. The consortium will benefit from its interdisciplinary composition represented by basic researchers and clinicians who tackle the competitive field of the tumor secretome by analyzing different tumor entities, i.e. ovarian cancer, prancreatic ductal adenocarcinoma and acute myeloid leukemia.
The Institute of Pharmacology is proud to be part of this consortium with a project on the “Influence of tumor-host secretome on ovarian cancer cell invasion and metastasis”.
Identification of dickkopf-3 as a novel predictive marker for acute kidney injury
Acute kidney injury (AKI) is the most frequent complication in patients who have cardiac surgery. However, preoperative diagnostic markers for the identification of patients at high risk for postoperative loss of kidney function are missing. Hermann-Josef Gröne now contributed to a study published in “Lancet”, which shows that preoperative urinary dickkopf-3, a modulator of the Wnt/β-catenin signaling pathway, is an independent predictor for postoperative AKI. This could allow preventive strategies in patients at high risk for AKI.
After a fascinating guided tour through the beautiful Marburg castle, we enjoyed the wonderful weather with barbecue and beer. Cheers!
June 2019
Glycosphingolipids as novel pharmacological targets in acute kidney injury
A new publication of the research team of Hermann-Josef Gröne shows that globotriaosylceramide (Gb3/CD77), a glycosphingolipid expressed in tubular epithelial cells of the kidney, could be a potential new pharmacological target in the treatment of acute kidney injury.
Frank Czubayko and Thomas Worzfeld receive the Award for Excellent Teaching of the State of Hesse
Foto: Nadja Düvelmeyer
von links nach rechts - Nora Jochens, Chirurgische Klinik; Dr. Andreas Jerrentrup, Zentrum für Notfallmedizin; Dr. Martin Sassen, Zentrum für Notfallmedizin; Prof. Frank Czubayko, Pharmakologisches Institut; Angela Dorn, Ministerin für Wissenschaft und Kunst des Landes Hessen; Prof. Thomas Worzfeld, Pharmakologisches Institut; Prof. Katharina
Krause, Präsidentin der Universität Marburg; Prof. Stefan Bösner, Abteilung für Allgemeinmedizin; Prof. Hinnerk Wulf; Klinik für Anästhesie; Dr. Egbert Opitz, Leiter des Marburger Kurses Patientensicherheit
from left to right - Nora Jochens, Department of Surgery; Dr. Andreas Jerrentrup, Department of Emergency Medicine; Dr. Martin Sassen, Department of Emergency Medicine; Prof. Frank Czubayko, Institute of Pharmacology; Angela Dorn, Minister of Science and Art of the State of Hesse; Prof. Thomas Worzfeld, Institute of Pharmacology; Prof. Katharina Krause, President of the University of Marburg; Prof. Stefan Bösner, Department of General Medicine; Prof. Hinnerk Wulf; Department of Anesthesiology; Dr. Egbert Opitz, Manager of the Patient Safety Teaching Programme
The Award for Excellent Teaching of the State of Hesse 2019 goes to the teaching project “Decide wisely – treat safely” of the University of Marburg. As part of a team of 22 members of the Medical Faculty, Frank Czubayko and Thomas Worzfeld received the award on May 16th 2019 from Angela Dorn, the Minister of Science and Art of the State of Hesse.
On May 16th and 17th, we had a joint retreat of the Biochemical-Pharmacological Center and the Marburg Graduate School on “Membrane Plasticity” at the picturesque Castle Rauischholzhausen. 11 research groups of the Faculties of Medicine, Pharmacy and Biology of the University of Marburg spent two fascinating days with great talks and intense and fruitful discussions. An exciting collaborative meeting, made possible by the generous funding of the UMR 2027 initiative of Marburg University!
May 2019
Defense Laura Soto Hinojosa
Foto: Sylvia Krippner
On Tuesday, May 14th, 2019, Laura Soto Hinojosa successfully defended her thesis with the title „MRTF/SRF-dependent transcriptional regulation for bleb-associated cell invasion and entosis”.
Congratulations, Laura, and all the best for your future research as Postdoc at the Centre for Genomic Regulation (CRG) in Barcelona!
February 2019
Tumor-associated macrophages play an important role for the synthesis of lysophosphatidic acid (LPA) in the ovarian cancer tumor microenvironment
A research team of the University of Marburg and the Max-Planck-Institute for Heart and Lung Research, including Dominique Brandt, Robert Grosse and Thomas Worzfeld, discovered that the concentrations of lysophosphatidic acid (LPA) in the ascites of ovarian cancer patients are strongly elevated. This correlates with patient survival. Further analyses showed that tumor-associated macrophages crucially contribute to lysophosphatidic acid (LPA) synthesis.
