We are interested in survival of mature B cells after deletion of components of B cell antigen receptor (BCR) and its signaling machinery. For this purpose we are using Tamoxifen-inducible B cell specific Cre strains to delete different “floxed” alleles (immunoglobulin heavy chain, Iga, Igb, Syk) in B cells. Furthermore, we would like to translate our knowledge to murine and human B cells from established mouse models for malignant B cell development and from human patients with lymphatic disorders mainly chronic lymphocytic leukemia (CLL) respectively.
CLL is a frequent lymphoproliferative disorder of B cells. Although inhibitors targeting signal proteins involved in B cellantigen receptor (BCR) signaling constitute an important part of the current therapeutic protocols for CLL patients, the exact role of BCR signaling, ascompared to genetic aberration, in the development and progression of CLL is still controversial. We are currently investigating whether BCR expression per se is pivotal for thedevelopment and maintenance of CLL B cells, which we used in the TCL1 mouse model.
Furthermore, we are testing, whether mutations augmenting B cell signaling influencethe course of CLL development and its severity. The Phosphatidylinositol-3-kinase(PI3K) signaling pathway is an integral part of the BCR signaling machinery and its activity is indispensable for B cell survival. It is negatively regulated by the lipidphosphatase PTEN, whose loss mimics PI3K pathway activation. Our studies focus on the pivotal role for BCR signaling in CLL development and deepen our understanding of the molecular mechanismsunderlying the genesis of CLL and for the development of new treatment strategies.
Dr. Andreas Neueder
Dr. Andreas Neueder is a postdoctoral fellow in the Department of Neurology (Head: Prof. Albert Ludolph, PI: Prof. Bernhard Landwehrmeyer). His main interest is RNA based molecular mechanism leading to neurodegeneration, in particular RNA toxicity in CAG repeat disorders.
Shorter versions of huntingtin (HTT), the disease-causing gene in Huntington's disease (HD), have been detected in post-mortem brains from HD patients and mouse models of HD and a considerable amount of research highlights that these fragments play a crucial role in disease pathogenesis. Despite a huge amount of work, the exact nature of the fragments and the responsible proteases remain largely unknown. During his postdoc in the lab of Prof. Gillian Bates in London (KCL and UCL, London, UK), he could show for the first time that the smallest and most toxic fragment of HTT (exon 1 HTT) is produced by incomplete splicing of the HTT pre-mRNA and not through the action of proteases.
Dr. Neueder continues to investigate this phenomenon using a combination of molecular biology and systems biology approaches. The HD clinics in Ulm with its very large patient cohort allows for powerful analysis of clinical measures concomitantly with molecular readouts. To this end, Dr. Neueder generates and analyses 'big data' in the context of HD. These datasets come from various biological sources and are analysed using advanced network-based bioinformatics to evaluate and integrate the 'omics datasets.
Dr. Janis Müller
Dr. Janis Müller is a young investigator in the Institute of Molecular Virology (directed by Prof. Jan Münch and Prof. Frank Kirchhoff). He received his PhD in 2017 by the International Graduate School in Molecular Medicine for his work on the sexual transmission of HIV-1 and other viruses.
During his PhD, in 2015, Zika virus re-emerged to cause several outbreaks in the Americas. Infection with the virus can cause neurological complication like the Guillain-Barrée syndrome and most devastatingly teratogenic effects including fetal death and microcephaly upon infection during pregnancy. Atypically for this mosquito-transmitted virus, sexual transmissions have also been recorded and Janis Müller quickly took this virus in the focus of his research.
His work is concerned with the various transmission routes of Zika virus and how it can be prevented. Zika virus is found in plasma, saliva, urine, breast milk, semen, and vaginal fluid but how the body fluids influence its infectious potential is unclear. His research revealed that semen generally reduces flavivirus infectivity and that extracellular vesicles are responsible for this effect. The vesicles are highly abundant in semen and prevent the viral attachment to its target cells. He is now working with highly purified extracellular vesicles from various body fluids to characterize them for their composition and to understand the mechanism of viral interference.
Dr. Konstantin Sparrer
Dr. Konstantin Sparrer is a junior group leader and Marie-Curie fellow at the Institute of Molecular Virology (directed by: Prof. Frank Kirchhoff, Prof. Jan Münch). He joined the institute in the beginning of 2018 after his postdoctoral studies at the University of Chicago and Harvard Medical School. He completed his PhD at the Ludwig-Maximilians University in 2013.
His research focuses on the interplay of viruses and host, especially the cell-intrinsic innate immune system. Concerted action of multiple pathways, among them autophagy and the type-I interferon response, efficiently facilitate prevention and/or clearance of microbes such as viruses. His previous studies already revealed that many factors involved in the induction of autophagy have (at least) dual roles. For example, TRIM23 upregulates both autophagy and type-I interferon upon infection. While the anti-viral properties of the type-I interferon are well-characterized, autophagy is a self-digestive homeostatic pathway with an emerging role within the innate immune system.
Concerted activation of innate immune defence mechanisms requires coordinated activation and modulation. Key factors that coordinate multiple anti-viral pathways represent hubs in the innate immune network, or short: immunohubs. These factors define our anti-viral responses and are thus major determinants of infectious diseases. We aim to discover novel immunohubs to gain insight into regulation of our network of interconnected immune defences and examine their interplay with viruses and explore therapeutic modulation of anti-viral innate immunity.
Dr. Annabel Müller-Stierlin
Dr. Annabel Müller-Stierlin is a postdoctoral research fellow with a background in nutritional science and medical biometry working at the Department of Psychiatry and Psychotherapy II (head: Prof. Dr. T. Becker). She completed her PhD thesis in the field of integrated care for people experiencing severe mental illness. Over the last six years at the University of Ulm, Annabel has become familiar with health care research, health economics and implementation research.
Her primary research interest is the effectiveness, cost-effectiveness and process-outcome-evaluation of psychosocial interventions with a special focus on multi-professional teams and inter-professional collaboration. Since mental illnesses affect all areas of life, there is a need for health care services that comprise a wide range of professional disciplines. In order to provide care efficiently, it is not enough to bring together multi-professional teams, but inter-professional cooperation must be promoted through appropriate training and communication paths. Not only in mental health care, but also in research, a wide variety of disciplines must finally be united to answer important questions in psychiatry, such as antipsychotic-induced weight gain. Therefore geneticists and microbiologists should be involved in research teams besides medical doctors and health scientists.
By mediating between different professional groups, Annabel’s aim is to ensure inter-professional cooperation in care and research.
Dr. Katharina Ernst
Dr. Katharina Ernst is a young investigator working at the Institute of Pharmacology and Toxicology with Prof. Holger Barth on bacterial protein toxins. Her research focuses on the pathophysiological mechanisms of Bordetella pertussis toxins in the human airway epithelium for developing novel pharmacological strategies against toxin-mediated diseases.
Whooping cough is a severe childhood disease caused by infection of the airways by the bacterium Bordetella pertussis and its secreted toxins. Despite available vaccination, the world health organization reported ~16 Mio cases and 195,000 death due to whooping cough in 2008. Characteristic symptoms include severe coughing that usually lasts for several weeks and can lead to secondary complications like vomiting, pneumothorax, rib fractures and apnea which can be life threatening especially in newborns and infants. Since it is not well understood how pertussis toxins cause severe symptoms, Katharina will characterize the effects and underlying mechanisms of these toxins in a human primary airway epithelium model at air liquid interface conditions. Katharina is a PI in the DFG research training group PULMOSENS and within this project, novel electrochemical microbiosensors will be developed in collaboration with Prof. Christine Kranz (Institute of Analytical and Bioanalytical Chemistry) to analyze effects of pertussis toxins in the human airway epithelium.
Currently, there are no therapeutic options available to treat patients suffering from severe whooping cough symptoms. That is why Katharina’s research also focuses on developing novel pharmacological strategies against toxin-mediated diseases. Therefore, two strategies are pursued: (i) small molecule inhibitors of protein folding helper enzymes that are required for the mode of action of pertussis toxin and (ii) screening of human peptide libraries within the CRC 1279 to identify inhibitory peptides against pertussis toxins. Her further project with a focus in trauma research is associated with the CRC 1149.
Dr. Tamara Merz
Dr. Tamara Merz is a postdoctoral research fellow working in the Institute of Anesthesiological Pathophysiology and Process Engineering (Head: Prof. Dr. Peter Radermacher). Her research interest is the role of the endogenously produced gaseous mediator hydrogen sulfide (H2S) in the context of stress/trauma and circulatory shock.
Circulatory shock is characterized by the failure of the circulatory system to meet the requirements of oxygen and energy substrates of the organism, leading to inadequate cellular oxygen utilization and multiple organ failure. The reduced oxygen utilization leads to a metabolic switch from mitochondrial oxidative phosphorylation to anaerobic glycolysis (Warburg effect). Hyperglycemia is an essential survival response, however it can be associated with higher mortality related to increased oxidative stress and mitochondrial damage. H2S is involved in both glucose regulation and mitochondrial respiration and it can have anti-oxidative and anti-inflammatory effects. The maintenance of H2S availability might thus attenuate shock-related metabolic dysregulation. Exogenous H2S administration is a promising therapeutic option, however due to its narrow therapeutic window, further investigation is warranted. The preservation or upregulation of the endogenous H2S enzymes could represent an alternative therapeutic strategy.
Physiological and psychological trauma/stress share a plethora of biological characteristics. Thus, another research focus (in collaboration with the Clinic of Psychosomatic Medicine and Psychotherapy) is the recently identified interaction of H2S with oxytocin (OT): OT is a known player in psychological trauma and also involved in glucose metabolism regulation. Glucocorticoids (GCs) play a role in glucose metabolism and psychological trauma as well and seem to interact with the H2S and OT system (further research in collaboration with the Institute of Comparative Molecular Endocrinology). In pre-clinical and clinical studies, the investigation of the interaction of H2S, OT and GCs during psychological and physiological stress might help to identify novel therapeutic strategies.
Dr. Ina Vernikouskaya is a postdoctoral research fellow working in the Clinic of Internal Medicine II (head: Prof. Dr. W. Rottbauer).
Since 2010 Ina is working in the research group for experimental cardiovascular imaging headed by Prof. Dr. V. Rasche, first as a PhD student and then since 2015 as a postdoc. In addition to purely scientific work, between May 2011 and November 2012 (before she became a mother) she accompanied the development of the Core Facility Small Animal Imaging as a deputy head. She completed her PhD thesis in the field of methodological development of magnetic resonance imaging (MRI) for new application areas for human and animal experimental questions. After pursuing her doctorate degree, Ina became familiar with a completely new field of navigation of complex interventions and over the past two years has demonstrated the advantages of augmented navigation in a direct clinical context.
Transvascular procedures are commonly performed under x-ray (XR) fluoroscopy guidance. While providing high temporal and spatial resolution, XR lacks anatomical information. Multimodal intra-procedural three-dimensional (3D) image fusion (IF) can augment the limited information available from XR with relevant anatomic soft-tissue structures. With the available fusion packages on commercial x-ray systems, a wider range of transvascular catheter interventions can potentially be supported by IF. All commercial systems, however, are proprietary, and image data, position/tracking data, algorithms, and visualization methods are not made available for independent research. Therefore in order to introduce more advanced guidance techniques into the product functionality, such as e.g. automatic cross-modal image registration, image-based tracking, automatic real-time compensation of heartbeat and respiratory motion, and to perform research, development, and validation in the field of intraprocedural image guidance, independent IF software solutions appear of high interest. Therefore the purpose of her current work is to provide a rapid prototyping framework for integration of pre-interventional anatomical and functional data with real-time XR fluoroscopy and anatomically correct documentation of the working points in 3D.
Dr. med. Julia Zinngrebe is a young investigator working in the Department of Paediatrics and Adolescent Medicine.
Julia finished her studies of human medicine at Ulm University in 2014. From 2011 until 2013, she worked on her MD thesis project in the lab of Prof. Henning Walczak at University College London. Her project dealt with the question how linear ubiquitination, a certain type of post-translational modification, controls innate immune signalling mediated by Toll-like receptor (TLR) 3, and how a defect in linear ubiquitination leads to TLR3-induced autoinflammation and immunodeficiency (Zinngrebe, Rieser et al., JEM, 2016).
After completing her studies of human medicine, she joined the Department of Paediatrics and Adolescent Medicine in Ulm and continued her scientific career entering the field of paediatric leukaemia research. About every seventh patient with acute lymphoblastic leukaemia (ALL) during childhood suffers from relapse. Thus, new treatment options are urgently required. Julia evaluates the efficacy of therapeutic strategies interfering with the anti-apoptotic machinery of paediatric ALL cells. The prognosis of relapsed ALL is especially poor if the bone marrow is affected. This is why Julia also investigates how the bone marrow microenvironment influences leukaemia cell survival. As adipocytes account for up to 70 percent of the bone marrow, and given their role in the bone marrow niche of paediatric ALL is understudied and only poorly understood, Julia addresses the question how the survival and proliferation of leukemic blasts is influenced by adipocytes. Identification of possible interaction routes between adipocytes and leukemic cells shall help identifying new therapeutic targets, especially for those patients suffering from a bone marrow relapse.
Dr. Kerstin Felgentreff
Dr. Kerstin Felgentreff is a young investigator in the Clinic of Pediatric and Adolescent Medicine (head: Prof. Dr. K.-M. Debatin), Pediatric Stem Cell Transplantation, Rheumatology and Immunology. Her research focuses on DNA repair and primary immunodeficiencies.
DNA damage occurs ubiquitously in every cell triggered by e.g. endogenous factors of metabolism, or exogenous influences such as ionizing radiation or intercalating chemical drugs. Furthermore, DNA double strand breaks are physiologically induced in the process of V(D)J recombination or isotype class switch recombination for the generation of diversified T cell and immunoglobulin receptors in lymphocyte development. Dr. Felgentreff's current interest is to investigate the role of DNA damage response in lymphocyte development by differentiating induced pluripotent stem cells (iPSC) in vitro into lymphocytic lineages.
Another project focuses on an applicable test of DNA repair biomarkers to identify patients with DNA repair defects. Genetic defects affecting DNA repair proteins can cause various immunodeficiencies due to impaired lymphocyte development and survival. The only treatment option for many of these diseases is the allogeneic hematopoietic stem cell transplantation, although associated with increased toxicity to conditioning regimens. Early diagnosis of increased radio- and chemosensitivity has a tremendous impact on treatment decisions, in particular for patients identified with immunodeficiency at birth by newborn screening.
Dr. Felix Seyfried is a physician scientist in the Department of Pediatrics and Adolescent Medicine (Head: Prof. Dr. K.-M. Debatin). His major research interest is to elucidate aberrant activated survival pathways and deficient cell death signaling in B-cell precursor acute lymphoblastic leukemia (BCP-ALL), which is the most common malignancy in childhood and adolescence.
The dependency of leukemias on altered signaling pathways at diagnosis influences the disease evolution and the outcome of patients. The identification and monitoring of pathway alterations, which contribute to leukemogenesis or determine sensitivity or resistance of ALL cells to (targeted) therapy, will be useful to guide molecular therapeutic approaches. Pro- and anti-apoptotic members of the BCL-2 family proteins are key regulators of the intrinsic apoptosis pathway, therefore serving as potential targets for therapeutic intervention. Using synthetic pro-apoptotic peptides in a flow cytometry-based approach, BH3-profiling, developed by Prof. A. Letai (Dana-Farber Cancer Institute, Harvard Medical School, Boston), he identified a strong association of mitochondrial BCL-2 dependence with leukemia-free survival times after in vivo therapy of ALL patient-derived xenografts with the BCL-2-directed inhibitor venetoclax. However, some leukemias demonstrated resistance to the BCL-2 inhibitor by shifting their BCL-2-dependence to other molecules, such as BCL-XL or MCL-1. Thus, analyzing the functional interplay of mitochondrial apoptosis signaling parameters will enable to select patients who will benefit from treatment with a novel inhibitor. In current projects, dependencies of leukemias on pro-survival signals of apoptosis regulators are addressed at the functional level. The main goals of the research are to evaluate the efficacy of directed therapies in ALL, to identify mechanisms determining sensitivity or resistance and to establish strategies to predict treatment response of patients to targeted treatment prior to therapy.
Dr. Daniel Tews
Dr. Daniel Tews is a Postdoctoral Research Fellow at the Division of Pediatric Endocrinology and Diabetes (Head: Prof. Dr. Martin Wabitsch). His major focus is to understand the function and development of brown adipose tissue in children and adults.
Adipose tissue can be assigned to two clearly distinct subtypes, mainly based on its functional properties. White adipose tissue (WAT) is the major organ for energy storage, whereas brown adipose tissue (BAT) utilizes energy sources such as fatty acids and glucose to produce heat in a process called non-shivering thermogenesis. In contrast to earlier observations, it is now well accepted that BAT in humans is functionally active not only in neonates, but also in adults. Clinical studies have shown that BAT activity is negatively associated with body weight. In addition, activation of BAT results in an amelioration of body insulin sensitivity.
Interestingly, brown-like adipocytes can emerge in white adipose tissue depots upon chronic cold exposure or beta-adrenergic treatment, a process usually termed “browning” or “britening”. As a matter of debate, these adipocytes can either differentiate de novo from a distinct precursor pool or convert from preexisting white adipocytes.
We are currently interested in transcription factors and secreted proteins that drive brown adipogenesis in humans.
Dr. Tews is funded by the DFG and the Boehringer Ingelheim University Ulm Biocenter (BIU, link BIU C5). Moreover, he is deputy head of the core unit “Extracellular Flux Analyzer” (link).
Dr. med. Alpaslan Tasdogan
Dr. med. Alpaslan Tasdogan is a postdoctoral fellow at the Institute for Immunology (PI: Prof. Hans Jörg Fehling) and is also a participant of the Dermatology Residency Programme at the University Hospital Ulm. Recently, he has received an Else-Kröner Fresenius fellowship for clinician scientist. Dr. Tasdogan is partially responsible for the Flow Cytometry Core and developing novel flow cytometric techniques at his institute.
His current interest is dissecting hematopoietic defects in Mixed-lineage-Leukemia-5-deficient mice and cell lines. Mixed-Lineage-Leukemia-5 (MLL5) is a distant and understudied member of the MLL/Trithorax gene family of epigenetic regulators. Classical members of this family (MLL1 – MLL4) are known to exhibit histone H3K4 methyltransferase activity and to be critically involved in normal hematopoiesis as well as hematopoietic malignancies. Along this line, human MLL5 is located in a genomic region (chromosome 7q22) recurrently deleted in leukemic cells from patients with aggressive forms of acute myeloid leukemia (AML). This initial observation has given rise to the view that MLL5 might exhibit tumor suppressor activities. However, no direct role of MLL5 in leukemogenesis has been documented so far, and also physiological roles of MLL5 are still poorly understood. The analysis of adult Mll5-deficient mice, generated in our own and two other laboratories, has revealed a variety of phenotypic abnormalities, including infertility, retarded growth and severe defects in hematopoiesis – a combination of traits often found in mouse mutants with defective DNA double strand break repair. Moreover, hematopoietic stem/progenitor cell compartments were functionally severely compromised.
With over 5 years of research experience in stem cell biology, gene targeting, hematopoiesis, and immunology, my current research goal is to develop and translate efficient stem cell based therapies for the treatment of cancer and genetic diseases that effect the hematopoietic system.
My main research philosophy relies on the idea that creative thinking and collaboration are the basis of scientific innovation that leads to new successful therapies for disease.
Dr. Astrid Pfister
Wnt signaling regulates cell growth, proliferation and differentiation and thus plays a crucial role in development and disease (MacDonald, 2009). Canonical Wnt ligands activate the Wnt/b-catenin pathway and drive the expression of Wnt target genes regulating e.g. cell proliferation and apoptosis (MacDonald, 2009). Consistently, it has already been demonstrated that several anti-apoptotic Wnt targets are up-regulated in tumors with constitutively active Wnt signaling, for instance in colon cancer and leukemia (Sansom, 2007). Thus, we study the cellular and molecular mechanisms underlying Wnt-mediated tumorgenesis. In particular, we focus on anti-apoptotic Wnt target genes by molecular biology methods and in vitro cell-culture assays on primary, cancer and acute myeloic leukemia (AML) cell lines. We will investigate the Wnt target nucleophosmin (NPM) in more detail, which is commonly mutated (35%) or mis-expressed in AML patients (Colombo, 2011) and will screen for novel candidates that are relevant for tumor biology.
Dr. Verena Gaidzik
Dr. Verena I. Gaidzik works in the department of internal medicine III (Head Prof. H. Döhner) as clinical fellow. Her research projects take place in the research group of Prof. K. Döhner (Head of the molecular and cytogenetic laboratory). Dr. Gaidzik is mainly responsible for the molecular diagnostics in the laboratory. Major focus of Dr. Gaidzik's research interest is elucidating the underlying mechanisms of acute myeloid leukemia (AML) by the identification of new genetic aberrations as well as their evaluation of their prognostic and predictive relevance in AML patients. Most of the scientific projects of Dr. Gaidzik are embedded in the framework of prospective clinical AML trials of the German-Austrian AML Study Group (AMLSG). Thus, she was able to analyze molecular markers like WT1, RUNX1, TET2, DNMT3A in large patient cohorts with regard to their mutation incidence and found out their associations with specific clinical and genetic characteristics. Furthermore, these studies aim to optimize the classification systems of AML patients and therefore also guide new and more specific treatment options. Another task is to improve the survival of AML patients by prediction and identification of patients with high risk of relapse. This is possible due to investigation of minimal residual disease (MRD) during therapy and follow-up. Currently, she works on the establishment and integration of DNMT3A mutations as a new MRD marker. In the SFB 1074 "Experimental Models and Clinical Translation in leukemia" she serves as a project leader. In this project Dr. Gaidzik is investigating a novel recurrent micro-deletion in the chromosomal band 3p14.1-p13 recently identified in cytogenetically-normal AML patients by single nucleotide polymorphism-array analyses. The commonly deleted region contains 8 protein-coding genes and one microRNA and will further be characterized by functional and (epi)-genetic analyses. The detected (epi)-genetic findings will be correlated with clinical characteristics and survival.