Translationale PhD-Projekte 2014
Targeting alternative translational initiation of oncogenes in cancer cells
Main supervisor: Prof. Dr. Matthias Selbach, MDC
Second supervisor: PD Dr. Patrick Hundsdörfer, Charité
Student: Joao Miguel Parente Fernandes, Helmholtz Graduate School Molecular Cell Biology, MDC
Project summary: We aim to evaluate mechanisms of internal ribosomal entry site (IRES)-mediated translation as an innovative avenue towards new cancer treatment strategies. IRES-mediated translation represents an alternative protein synthesis method used by tumor cells to maintain oncogene expression even during cellular stress, when global (cap-dependent) translation is impaired. This complex posttranscriptional regulation mechanism is controlled by IRES trans-acting factors including EIF4G2 and MDM2. Interestingly, among the limited number of eukaryotic mRNAs harboring IRESes, several encode important oncogenes. Based on data obtained in previous projects, we aim to validate (i) IRES-regulated translation as a general survival mechanism of malignant cells and (ii) targeting of EIF4G2 and MDM2 as an efficient and promising new treatment strategy simultaneously inhibiting several major oncogenes in clinically relevant cancers including neuroblastoma.
Dissecting the cellular and molecular mechanisms of leukemia cell migration and localization to and within the testis in childhood ALL
Main supervisor: PD Dr. Uta E. Höpken, MDC
Second supervisor: Dr. Cornelia Eckert, Charité
Student: Tessa Lara Skroblyn, Helmholtz Graduate School Molecular Cell Biology, MDC
Project summary: The pathomechanisms of testicular involvement at relapse of pediatric acute lymphoblastic leukemia (ALL) are not yet known. Current treatment recommends surgical removal of the clinically involved testis and chemotherapy. Orchiectomy is invasive and impacts long-term quality of life. This project will dissect cellular requirements and molecular pathways contributing to leukemic cell dissemination to the testes and tumor-stroma crosstalk in the testis. Chemokine receptor and adhesion molecule expression will be comparatively assessed on leukemic cells from patient bone marrow and testicular samples. Stromal elements in the juvenile testis facilitating leukemic cell migration and survival will be identified, and we will develop a mouse and/or rat model for pediatric ALL with testicular involvement. Basic and clinical research will interact bidirectionally with the aim to feed into new clinical trials to improve long-term event-free survival in boys with childhood ALL.
The role of human microglia for glioma progression
Main supervisor: Prof. Dr. Helmut Kettenmann, MDC
Second supervisor: Prof. Dr. Christoph Harms, Charité
Student: Amanda Luisa de Andrade Costa, International Graduate Program Medical Neurosciences, Charité
Project summary: Malignant gliomas, the most common subtype of primary brain tumors, are aggressive, highly invasive, and neurologically destructive, with poor prognosis for the patients and very limited treatment options. Glioma associated microglia and infiltrating macrophages (GAMs) are the largest population of tumor infiltrating cells, both in intact and in necrotic areas, and there is a direct correlation between their density and glioma grade and invasiveness. The presence of microglia is known to facilitate glioma growth, invasion and the establishment of an immunosuppressive milieu. The current treatment mainly targets the tumor and neglects the stromal cells and thus presents unsatisfying results. This highlights the need for deeper insights into the role of resident microglia versus infiltrating monocytes/macrophages in glioma.
Investigation of the energy expenditure of human iPSC-derived basal ganglia neurons from patients with Leigh Syndrome
Main supervisor: Dr. Alessandro Prigione, MDC
Second supervisor: Prof. Dr. Markus Schülke-Gerstenfeld, Charité
Student: Carmen Lorenz, Helmholtz Graduate School Molecular Cell Biology, MDC
Project summary: Leigh syndrome (LS) is a devastating infantile neurodegenerative disease caused by mutations of mitochondrial-related nuclear genes or alterations of mitochondrial DNA (mtDNA) genes. Due to the lack of viable models, the mechanisms underlying the pathognomonic demise of basal ganglia GABAergic neurons remain to be elucidated. Moreover, no cure or effective treatments exist. Here, we aim to develop novel modeling tools for LS by generating non-integrative induced pluripotent stem cells (iPSCs) from LS patients carrying both nuclear and mtDNA mutations. iPSCs will be differentiated into GABAergic basal ganglia neurons and detailed mitochondrial and metabolic investigations will be carried out to unveil disease-associated neuronal phenotypes. High-throughput assays will be then set up to enable focused compound screenings on patient-derived neurons. This iPSC-driven approach may shed light on the pathogenetic mechanisms of LS and potentially pave the way to innovative treatment discovery.
RNA-edited glycine receptor as marker and therapeutic target in intractable epilepsy
Main supervisor: Prof. Dr. Martin Holtkamp, Charité
Second supervisor: Prof. Dr. Jochen Meier, MDC
Student: Larissa Kraus, International Graduate Program Medical Neurosciences, Charité
Project summary: RNA editing recently emerged as a key mechanism in maladaptive plasticity in epilepsy. We focus on the RNA-edited glycine receptor (RNA-GlyR), which showed an increased expression in resected hippocampi of epilepsy patients. In a corresponding mouse model with increased expression of RNA-GlyR we found altered neuronal excitability as well as cognitive and psychiatric abnormalities similar to those found in epilepsy. In our project, we propose to identify specific RNA-GlyR antagonists by high throughput screening and to validate the therapeutic potential of the identified substances using the abovementioned mouse model and resected brain tissue from patients with epilepsy. Experiments will include slice electrophysiology, optical imaging, as well as molecular methods and behavioral tests. A successful validation of RNA-GlyR antagonists as antiepileptic drugs in human brain tissue may pave the way towards clinical trials and culminate in a novel strategy to treat intractable epilepsy.
Identifying the mechanisms of antidepressant drug action in mice lacking brain serotonin
Main supervisor: Prof. Dr. Golo Kronenberg, Charité
Second supervisor: Prof. Dr. Michael Bader, MDC
Student: Markus Petermann, Helmholtz Graduate School Molecular Cell Biology, MDC
Project summary: Serotonin deregulation plays a physiologic role in neurogenic decline and mood disorders. In the case of depression, manipulation of serotonin leads to clinical improvement associated with a delayed increase in hippocampal neurogenesis and BDNF signaling. However, commonly used serotonin-based antidepressants are broadly acting and we still lack a clear understanding of the underlying therapeutic mechanisms. We propose new insights that will come from examining the contribution of serotonin to the effects of pro-/anti-depressive stimuli on candidate mechanisms in the brain and behavior. We will take advantage of the Tph2-/- mouse model that lacks brain serotonin and explore the responds to i) antidepressant treatment, ii) psychological stress (chronic stress paradigm), and iii) electroconvulsive therapy. Identifying the pathways of serotonin activity, BDNF, and other neurotransmitter systems that directly mediate hippocampal neurogenesis can be used to define new therapeutic targets. The long-term goal is to identify antidepressant mechanisms and to facilitate a design of alternative approaches for the treatment of depression or age-related decline in learning and memory.
Modulation of neonatal olfactory cortex spontaneous synchronized activity in the GLUK2 KO model of mental retardation
Main supervisor: Dr. Friedrich Johenning, Charité
Second supervisor: Dr. James Poulet, MDC
Student: Laura Moreno Velasquez, International Graduate Program Medical Neurosciences, Charité
Project summary: Cortical activity in the pre- and postnatal period is dominated by spontaneous synchronized cortical waves. Patterns of these early network events affect neuronal development. It is not well understood how neurodevelopmental disorders affect spontaneous synchronized cortical waves and how these changes are related to phenotypes observed later in development. The aim of this proposal is to understand this relationship and explore ways of modifying early network activity patterns to interfere with disease related mechanisms. The transgenic mouse disease model we want to study in this project is the ionotropic kainate type glutamate receptor 2 (GRIK2 or GLUK2) knock-out mouse. A loss of function mutation of GLUK2 has been linked to nonsyndromic mental retardation in humans. We want to focus our study on activity patterns in the piriform or primary olfactory cortex, a brain region with high GLUK2 expression and a prominent pacemaker for spontaneous cortical waves early in development.
Impact of energy metabolism on bone regeneration
Main supervisor: Dr. Stefan Kempa, MDC
Second supervisor: Prof. Dr. Georg N. Duda & Dr. Anke Dienelt, Charité
Student: Julia Löffler, Berlin-Brandenburg School for Regenerative Therapies, Charité
Project summary: Fracture healing is a highly orchestrated process, triggered by the appearance of different cell types (immune cells, stem/progenitor cells) that quickly need to adapt to the altered environment found in injured bone. There is growing evidence that cells are sensitive to metabolic reprogramming by nutrient sensitive modifications of transcriptional active proteins, which allows modulating cell metabolism, proliferation and differentiation according to the metabolic resources. This highlights the possibility that accessible nutrients and the metabolic microenvironment within the regenerative tissue affects the phenotype of cells immigrating into the injured bone and hence influences the healing outcome. In this project the local metabolic conditions will be analyzed by metabolomics and proteomics at different stages under normal and impaired healing conditions. Obtained results will be connected to the existence of different cell subsets, surrounding mechanical conditions and age.
Regulation of pro- and anti-inflammatory mechanisms mediated by fatty acid metabolites in metabolic liver damage – a role for omega-3 fatty acids in prevention?
Main supervisor: PD Dr. Karsten-H. Weylandt & Dr. Ulrich-F. Pape, Charité
Second supervisor: Prof. Dr. Friedrich C. Luft & Dr. Wolf Hagen-Schunck, MDC / ECRC
Student: Mirjam Karber, International Helmholtz Research School Transcard, MDC
Project summary: Studies in children with short bowel syndrome and need for total parenteral nutrition (TPN) indicate that omega-3 fatty acids can protect from metabolic liver disease. This could be due to a combination of the promotion of lipid oxidation (indicated by their well-established effect to lower triglycerides), as well as their role as precursors of omega-3 derived lipid mediators with potent biological action. The proposed PhD project aims to establish lipidomic and metabolomic approaches in the Charité adult short bowel syndrome patient cohort in order to analyse lipid mediators, markers of inflammation and fatty acid metabolism. The aim is to identify and then test lipid metabolite compounds for direct pharmacologic interventions in vitro and in animal experiments. While the short bowel syndrome is a rare clinical entity, this approach may also serve as a clinical model for mechanisms involved in the highly prevalent condition of non-alcoholic fatty liver disease (NAFLD).
Functional characterization of osteoactivin/Gpnmb in myocardial infarction
Main supervisor: Prof. Dr. Michael Bader, MDC
Second supervisor: Prof. Dr. Karl Stangl, Charité
Student: Bernadette Nickl, International Helmholtz Research School Transcard, MDC
Project summary: We have found increased levels of Gpnmb in rodents and humans after myocardial infarction. Therefore this protein may be of high diagnostic or therapeutic value for this disease with highest mortality. The PhD project will evaluate this potential inn genetically altered mouse model and patients and has therefore strong translational relevance based on the high medical need for additional diagnostic tools and therapeutic approaches to improve the care of infarct patients.