The projects outlined on this page were selected for funding in June 2015 (please find further information on Translational PhD Project Grants here).
Modulation of muscle afferent mechanotransduction to treat painful muscle pathologies
Main supervisor: Prof. Gary R. Lewin, MDC
Second supervisor: Prof. Michael Schäfer, Charité
Student: Johannes Kühnemund, Helmholtz Graduate School Molecular Cell Biology, MDC
Project summary: Chronic muscle pain following tissue injury and genetic diseases is a serious clinical problem. The muscle sensory innervation is composed of proprioceptors and specialized nociceptors that detect harmful stimuli that trigger pain. The activation and sensitization of muscle nociceptors can cause much longer lasting hyperalgesia than equivalent activation of skin nociceptors. The hypothesis to be tested here is that muscle nociceptor sensitization is dependent on modulation of their mechanosensitivity. Recent progress has been made in identifying molecules that are involved in transforming mechanical stimuli into electrical signals (mechanotransduction). However, the relevance of sensory mechanotransduction molecules is unexplored for the muscle innervation. Here the PhD candidate will use a novel ex vivo muscle-nerve model to test the role of mechanotransduction molecules like Piezo2 and STOML3 on the sensitization of single muscle nociceptors under normal and pathological conditions.
Investigating mechanisms of microglia-mediated neuronal damage processes in Multiple Sclerosis pathophysiology
Main supervisor: Dr. Volker Siffrin, Charité
Second supervisor: Prof. Helmut Kettenmann, MDC
Student: Tadhg Crowley, International Graduate Program Medical Neurosciences, Charité
Project summary: Neuronal damage is the correlate for long-term disability in patients suffering from Multiple Sclerosis. Here we would like to investigate the involvement of microglia and macrophages in the processes leading to damage at the axon-oligodendroglial unit by use of intravital imaging of damage mechanisms and by human in vitro culture models. We aim to monitor the complex processes of the immune cell attack onto myelinated axons and delineate the chain of cause and effect. We will employ transgenic mice which express distinct fluorescent molecules in microglia and macrophages and report Ca2+ dynamics in the neuronal compartment, which gives a functional read-out of these processes. In vivo imaging will rely on semi-quantitative measurement of neuronal Ca2+ fluxes in EAE lesions of anaesthetized mice, which carry a Ca2+ sensor protein. The vision of this project is to open up new perspectives to specifically target immune-mediated neuronal damage processes in inflammatory CNS disease.
Decoding the metabolic program of deregulated MYCN expression in neuroblastoma
Main supervisor: PD Dr. Hedwig Deubzer, Charité
Second supervisor: Dr. Stefan Kempa, MDC
Student: Birte Arlt
Project summary: MYCN oncogene amplification occurs in 20% of neuroblastomas (NBs) and is a hallmark of high risk. Prognosis of MYCN-amplified NB has remained unfavorable despite intensive multimodal therapy. As a member of the MYC family of oncoproteins, deregulated MYCN expression is a major driver force of neuroblastomagenesis. We showed that elevated energy consumption and addiction to mitochondrial glutaminolysis in cells expressing dere-gulated MYC establish a dependence on the kinase ARK5. Similar phenomena may be anticipated in regard to MYCN. No approaches using metabolomics for the study of MYCN in NB have been published to date. We here intend to identify key metabolic pathways in the energy-, lipid- and carbohydrate metabolism perturbed by MYCN as a potential new class of target molecules for NB therapy in synthetic MYCN-inducible cell lines and in MYCN-amplified cells depleted of endogenous MYCN expression by transient expression of a short hairpin RNA plasmid directed against MYCN.
Placental and cardiovascular maladaption during preeclampsia as a risk factor for future cardiovascular disease
Main supervisor: Prof. Dominik N. Müller, MDC / ECRC
Second supervisor: PD Dr. Stefan Verlohren, Charité
Student: Kirstin Kräker, International Helmholtz Research School Transcard, MDC
Project summary: Cardiovascular disease (CVD is the leading cause of death of men and women in developed countries and most emerging economies. It is a substantial burden to individuals and societies and its prevention remains a global challenge. In addition to classic, gender-independent risk factors for CVD, pregnancy complications are sex-specific risks. The American Heart Association proposed preeclampsia (PE) as a risk factor for developing CVD. PE complicates about 5% of all pregnancies worldwide and is the major cause of maternal and fetal morbidity and mortality. Long-term morbidity has also been observed in former preeclamptic mothers, with the development of an increased risk of cardiovascular conditions. Little attention paid to unraveling mechanisms for the risks of young women with pregnancy complications. The purpose of the proposal is to investigate the role of cardiovascular function in preeclampsia during and after pregnancy in humans and in an established rat model for preeclampsia.
Novel gene therapeutic approaches to osteopetrosis
Main supervisor: Prof. Uwe Kornak, Charité
Second supervisor: Dr. Zsuzsanna Izsvak, MDC
Student: Ute Rössler, Berlin-Brandenburg School for Regenerative Therapie, Charité
Project summary: Autosomal recessive osteopetrosis (ARO) is a lethal disorder due to dysfunctional osteoclasts resulting in impaired bone resorption. Allogenic hematopoietic stem cell (HSC) transplantation as the only curative treatment still harbors considerable risks. Here, we aim at developing strategies to transplant genetically complemented autologous HSC in the Clcn7-/- osteopetrotic mouse model. In order to minimize potential safety issues the strategies used for additive gene transfer into primary HSCs are based on SB transposon. To aim at clinical translation, we will perform in vitro gene transfer experiments in primary human osteoclast progenitors from ARO patients and HSCs. In a parallel in vitro approach we will generate induced pluripotent stem cells (iPSCs) from CLCN7-related osteopetrosis patients and correct the individual genetic defect using genome editing. After selection and characterization these cells will be differentiated into osteoclasts to prove the restoration of function.
Study of novel molecular defects in human pancreas dysfunction
Main supervisor: Dr. Francesca M. Spagnoli, MDC
Second supervisor: PD Dr. Klemens Raile, Charité
Student: David Willnow, International Helmholtz Research School Transcard, MDC
Project summary: Understanding the complex nature of diseases is a key goal of both systems and personalized medicine. Our research focuses on human inherited diabetes, whose underlying pathogenetic mechanisms remain obscure. Unelucidated forms of monogenic diabetes represent invaluable models for identifying new targets of β-cell development and function. Through NGS of a unique cohort of families with rare diabetes we have identified four individuals with novel heterozygous HDAC4 mutations. HDACs are well known epigenetic modulators with critical functions in development and tissue homeostasis. We propose an interdisciplinary approach to study the HDAC4 regulatory network in β-cell identity, function and dysfunction. Ultimately, this study will set the stage for systematic dissection of disease mechanisms underlying severe neonatal diabetes, but also instruct translational efforts towards new treatment of diabetes.
Epigenetic disturbances contribute to the etiology of Preeclampsia
Main supervisor: Dr. Zsuzsanna Izsvák, MDC
Second supervisor: PD Dr. Ralf Dechend, Charité
Student: Katarina Stevanovic, Helmholtz Graduate School Molecular Cell Biology, MDC
Project summary: Preeclampsia (PE) is defined by high blood pressure and albuminuria. PE affects ~8% of human pregnancies, and remains a leading cause of maternal and perinatal mortality. In contrast, PE is not reported from other mammalian species. The etiology of PE remains uncertain and the only treatment is infant delivery. Our large-scale analysis based on microarray, miRNA, RNAseq and clinical data suggests that PE is not a single, but a heterogeneous disease of the placenta. In a subset of patients, epigenetic changes result in deregulation of imprinted genes, endogenous retroviruses (ERVs), and ncRNAs. Intriguingly, the aberrant expression of a human specific pregnancy-specific glycoprotein gene cluster is wired to an ERV family. These global abnormalities disturb a proper cross-talk between maternal and foetal. We assume that the epigenetic subgroup of PE, alternative splicing/transcription initiation is genome-widely deregulated, resulting in aberrant trophoblast proliferation and invasion.
Dissection of GvHD and tumor rejection by selective inhibition of NFAT-activation and gut-migration of adoptively transferred T cells
Main supervisor: PD Dr. Il-Kang Na, Charité
Second supervisor: Prof. Thomas Blankenstein, MDC
Student: Andreas Heimann
Project summary: Adoptive T cell therapy (ATT) is a promising tool in cancer therapy. However, treatment of large solid tumors is hampered by factors secreted within the tumor microenvironment that inhibit T cell infiltration and effector function. Targetting a tumor antigen also expressed in distal tissues further harbors the risk of lethal graft-versus-host disease (GvHD).Using our unique dual bioluminescent reporter that allows monitoring of T cell migration and activation patterns in vivo, we plan to test two novel approaches to be used in combination with ATT for improved tumor rejection and mitigation of GvHD:1. Specific inhibition of T cell activation using the NFAT-inhibitor 11R-VIVIT2. Shifting the GvHD-GvT-balance by redirecting T cells away from intestinal GvHD effector sites using an antagonistic integrin α4β7-antibody. Systemic analyses of T cell migration and activation patterns will allow us to determine optimal treatment windows for these two promising cancer therapies.
Identification of interacting molecular Partners and their Role in human Physiology and Pathophysiology of Epithelial Transport
Main supervisor: Dr. Gunnar Dittmar, MDC
Second supervisor: Prof. Dominik Müller, Charité
Student: Lorena Artiles Suarez, Helmholtz Graduate School Molecular Cell Biology, MDC
Project summary: Epithelia constitute the barrier between different compartments in the body. This process is tightly regulated and controlled at various steps. Epithelial transport is provided by two different mechanisms, the transcellular and the paracellular pathway. The main structure for paracellular transport is constituted by the tight junction. Main components of this structure are claudins, a family that includes at least 24 members. Mutations in human claudin genes (CLDN) have been identified as disease causing due to altered epithelial function. In this project we seek to identify proteins that interact with and regulate claudins on a large scale basis. With special respect to this BIH translational PhD project, the PhD student will not only be involved in state-of-the-art proteomics and bioinformatics, but will be able to project molecular medicine to daily life of the patients and their families, and vice versa, thus, the desired interface of basic and clinical research.