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Weitere Programme der BIH Biomedical Innovation Academy
Translationale PhD-Projekte 2015
Modulation of muscle afferent mechanotransduction to treat painful muscle pathologies
Main supervisor: Prof. Dr. Gary R. Lewin, MDC Second supervisor: Prof. Dr. 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. Dr. Helmut Kettenmann, MDC Student: Tadhg Crowley, International Graduate Program Medical Neurosciences, CharitéProject 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 ArltProject 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. Dr. Uwe Kornak, Charité
Second supervisor: Dr. Zsuzsanna Izsvak, MDC
Student: Uta 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.