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. Melanie Haffner-Luntzer
Dr. Melanie Haffner-Luntzer is a Young Investigator in the Institute of Orthopaedic Research and Biomechanics (head of institute: Prof. Anita Ignatius). Her research focuses on molecular mechanisms involved in fracture healing, bone homeostasis and osteoporosis.
One of her projects is focusing on the pathomechanisms of delayed fracture healing in postmenopausal subjects. Besides the direct negative effects of estrogen-deficiency on bone formation, her previous work demonstrated a misbalanced inflammatory response after bone fracture. Inflammatory cytokines like Interleukin-6 and Midkine were significantly increased after fracture both in mice and human fracture patients. Future work will decipher the involved inflammatory cell types. The results may contribute to new therapeutic strategies to prevent healing complications in postmenopausal women.
Another project investigates the effects of chronic psychosocial stress on bone homeostasis and bone regeneration. This project is conducted in cooperation with the Laboratory for Molecular Psychosomatics (Prof. Stefan O. Reber) and is using the chronic subordinate colony housing mouse model combined with a standardized femur osteotomy model.
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. 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.
Jun. Prof. Dr. Karin Danzer
Jun. Prof. Dr. Karin Danzer, is a group leader in the Department of Neurology (Head: Prof. Albert Ludolph). Her research interest is elucidating the underlying mechanisms of different neurodegenerative disorders with a special focus in Parkinson's disease. Aggregation of alpha-synuclein and related toxicities play a central role in the development of Parkinson's disease. Recently, oligomeric and pre-fibrillar forms of alpha-synuclein have been identified as the toxic species in Parkinson's disease. Until recently, alpha-synuclein was thought to exert its toxic effects intracellularly. However, new data support an alternative possibility: that some forms of alpha-synuclein are secreted from, and taken up by neurons, and that this extracellular alpha-synuclein may be a toxic species. The goal of Dr. Danzer's research is to understand the underlying mechanisms of secretion, uptake of alpha-synuclein oligomers into neighboring neurons and propagation of alpha-synuclein pathology. Her special interest is not only the exosomal secretion of alpha-synuclein oligomers but also additional key proteins in neurodegenerative disorders like amyloid beta, Tau und SOD1. Using a wealth of biochemical, cell biological and molecular approaches, as well as analysis of patient samples and establishing new animal models Dr. Danzer hopes to understand underlying disease mechanisms and to identify not only new biomarkers but also additional and new factors contributing to neurodegeneration.
Dr. Susanne Kühl
Wnt signaling is required for kidney development and misregulation of Wnt contributes to congenital kidney disease. We investigated the potential role of non-canonical Wnt target genes such as Pes1 and Ppan during Xenopus renal development (Tecza et al., 2011). In our recent study, we analyzed Alcam during embryonic kidney development (Cizelsky et al., 2014). Expression analysis showed that alcam expression in the kidney is conserved across species (Gessert et al., 2008). Moreover, several studies demonstrated that alcam is regulated by non-canonical Wnt signaling (Gessert et al., 2008). Loss of function approaches demonstrated that Alcam is required for tubule formation. Additionally, we showed a similar expression pattern of alcam and the potential non-canonical Wnt receptor fzd3 in the pronephros and that Fzd3 acts upstream of alcam. Importantly, we also demonstrated that alcam is a direct target gene of non-canonical Wnt signaling. Our data set up a novel mechanism demonstrating a Fzd3/JNK/Alcam branch regulating tubular development in the embryonic kidney. In cooperation with Seppo Vainio, Oulu, Finland, we furthermore examined the regulation of wnt4 by Wt1 and Sox11 on a transcriptional level (Murugan et al., 2012).
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. Diana Lieber
Herpesviruses are widespread pathogens whose prevalence can reach far beyond 90%. There are eight human herpesviruses known which cause a great number of diseases including herpes labialis (cold sores), varicella (chickenpox), infectious mononucleosis (kissing disease) and different kinds of cancer. Although herpesviruses strongly vary in their pathogenesis, they all share the ability to remain life-long persistent in the host after primary infection. In a quiescent state, the so-called latent phase, only few of the by far more than 100 viral genes are active. Their main function is to maintain latency and to suppress the host’s immune reaction. However, a repeated reactivation with active virus replication is possible. This is mostly caused by distinct factors such as immune deficiency, hormones, stress or UV-irradiation. Antiviral therapeutics act usually on the replication of the viral genome and frequently select resistant viruses. Complete removal of herpesviruses from the host organism is currently not possible. Thus, virus carriers hold a life-long risk of reactivation and disease.
Our research addresses virus-host interactions in different human herpesviruses. A special focus lies on the function of cellular genes in human cytomegalovirus (HCMV) infection. We apply virological, genetic, cell biological and biochemical procedures. A key technology of the group is the so-called RNA interference which is used to silence single genes individually. This technology is adopted in one-by-one approaches as well as in systematic screenings. In addition, existing cell culture systems are tested with regard to their applicability in research on HCMV and other herpesviruses and new tailored transgenic cell lines are generated in order to improve the conditions for state-of-the-art experimental approaches and high-throughput screens.
Our aim is to better understand the molecular mechanisms underlying herpesvirus infections and to eventually find targets for innovative antiviral therapies.
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.