ECRT Projekte

Das ECRT will insbesondere den wissenschaftlichen Nachwuchs beim Aufbau eigener Forschungsvorhaben unterstützen. Dafür bietet das ECRT Einstein Kickboxen mit einer Startfinanzierung für erste Experimente zur Validierung der Forschungsideen sowie ECRT Research oder Consumable Grants zur Weiterentwicklung der Forschungsvorhaben.

Die Zusammenfassungen der Projekte stehen nur auf Englsich zur Verfügung.

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Frühere Einstein Kickbox Projekte

Einstein Kickbox Projects - Förderperiode 2018

A Quantitative Approach to ECM Function in Aged Muscle Regeneration – Towards Predictive Modeling of Cell-Matrix Interplay

Ageing affects the regenerative abilities of skeletal muscle resulting in compromised healing associated with fibrosis, impairing mobility and affecting quality of life. Current research is largely focused on intrinsic muscle stem cell function, but local extrinsic changes are mostly neglected. However, skeletal muscle repair relies on a dynamic interplay between muscle satellite cells (SCs) and the extracellular matrix (ECM) microenvironment. We have preliminary evidence for a transient developmental-like ECM during early phases of muscle regeneration. We believe that this creates a biomechanical three-dimensional micro-niche conducive to SC expansion, differentiation and self-renewal during regeneration, and that its derailment in aging or disease contributes to SC malfunction. However, the mechanical properties of the pro-regenerative ECM, especially during aging, has not been analyzed and the influence of the bio-mechanical properties of the aged ECM on stem cell behavior remains unclear. By combining experimental and mathematical analysis in an interdisciplinary approach, we aim to comparatively determine and quantify the dynamic spatio-temporal structure, composition and functionality of the transitory ECM in young and old mice. Iterative mathematical modeling via integration of biological data in a stepwise fashion will in the future develop a predictive landscape to achieve a new level of understanding of ageing processes prospectively transferable to muscle-degenerative disorders.

Team: Sigmar Stricker, Arunima Murgai, Georgios Kotsaris, Max von Kleist, Vikram Sunkara

Funding: Einstein Kickbox - Advanced Scientists

Alterations in endothelial cell mechanics affect nuclear morphology and chromatin conformation: the mechanogenomic code

In this project we aim to establish a new scientific research focus at the ECRT, mechanogenomics. Multiple redundant interactions connect the plasma membrane to the nucleus allowing for external mechanical forces to alter nuclear morphology, a process which has been shown to have influence on the positioning of chromatin within the nucleus. Chromatin that associates with the nuclear membrane, so called lamina-associated domains (LADs), contains mostly inactive genes. We therefore hypothesize that mechanical forces directly influence gene expression via re-positioning chromatin in 3D nuclear space. Alterations in the extracellular matrix (ECM) composition might therefore modulate gene transcription during disease and regeneration. Preliminary data with CRISPR/Cas9 edited BMP receptor mutant endothelial cells show striking changes in cellular mechanics, ECM and nuclear lamina composition, as well as increased F-actin bundling and tubulin acetylation, resulting in increased cellular tension and nuclear deformation. In this context, we suggest that altered BMP signaling accounts only for a subset of differential gene expression, while other genes are regulated as a consequence of nuclear adaptation to novel mechanical inputs. Here, we aim to characterize the nuclear modifications with classical biochemical techniques and combine this, together with genome-wide identification of LADs and the corresponding transcriptome. Understanding the changes in the underlying regulatory gene networks and the synergism between BMP and mechano-signaling would provide novel insights for basic science as well as opportunities to translate this knowledge towards future treatment options in the clinics.

Team: Petra Knaus, Stefan Mundlos, Michael Robson, Jerome Jatzlau

Funding: Einstein Kickbox - Advanced Scientists

Systems Biology pipeline for discerning the disease phenotype of chondrocytes in osteoarthritis of the knee

Osteoarthritis of the knee (OAK) is one of the top five most disabling conditions that affects more than one-­third of people over 65 years of age and over 100 million individuals globally. OAK is characterised by an erosion of the articular cartilage, which leads to inflammation and pain accompanied by joint stiffness and immobility. Despite its prevalence, the molecular mechanisms triggering OAK are poorly characterised and current therapies cannot halt-­ or revert OAK. Consequently, knee joint replacement is often the only rehabilitative intervention. While animal models of OAK exist, the causative mechanisms leading to cartilage erosion are poorly understood. It is often unclear which of the OA-­associated factors are causing the disease, and which are a consequence or a mere side-­effect of it. Backed by literature evidence and own preliminary results on chondrocyte dynamics, we hypothesise that a disease-­associated chondrocyte (DAC) phenotype exists in early OA, causing subsequent cartilage erosion. Thus, identifying and characterizing DACs would pave the way for personalized diagnostic and therapeutic strategies to tackle an unmet clinical need. Within this project, we will identify the transcriptome signature of DACs from a mixed sample (healthy + DAC + noise). To do this, sophisticated bioinformatics and mathematical tools will be developed and applied to new experimental data from early OA time points, ensuring that DACs are sampled. Candidate transcripts will be compared to previously reported early OA-­associated factors, which typically contain mixtures of causative and consequential factors.

Team: Vikram Sunkara, Annemarie Lang, Max von Kleist, Christoph Schütte, Birgit Sawitzki

Funding: Einstein Kickbox - Advanced Scientsits

Control of Human Tissue Homeostasis and Immunity by Helper T cells (TiSSueHeLP)

The human body is constantly challenged with manifold pathogenic, chemical and physical stimuli. One of the major tasks of the immune system is to distinguish between harmless and harmful challenges in particular at barrier sites such as the skin. How do local T cells in such situations sense “danger”, localize challenges at defined tissues or cells and finally dose and center a right suitable reaction? How are regenerative processes induced, and do they differ in the context of pathogen- versus non-pathogen-type challenges? It seems to be logical that while a virus-infected cell has to be eliminated by cytotoxic effector T cells, such a reaction would be unsuitable for cells that have been activated by harmless chemical or mechanical stress. The immune system has to tightly control any inexpedient cytotoxic T cell action in particular at barrier sites. However, it is so far not known, how the activation of non-cytotoxic T cells is regulated at barrier sites.

In this Einstein Kickbox application we aim to perform multidimensional cytometric and histological analyses on circulating and tissue resident T cells to decode and delineate the human universe of T cell subsets according to novel cell surface signatures we have identified in our prework. Based on the achieved results we aim in further future activities to characterize the function of non-cytotoxic helper T cells in human tissues in particular in response to non-pathogenic stressors.

Team: Andreas Thiel, Christos Nikolaou, Lucie Loyal, Kerstin Wolk, Demetrios Christou, Roland Lauster

Funding: Einstein Kickbox - Advanced Scientists

3D - ALL - The tumor microenvironment of ALL in a bone marrow model

The aim of the project is to set up an as possible true-to-life model to study the microenvironment of primary acute lymphoblastic leukemia (ALL) cells on cell survival and resistance development. It is planned to investigate the effect of different drugs especially on the microenvironment but also on the ALL cells. While most cancer research focuses mainly on the pharmaceutical impact on tumor cells, the approach of this project will concentrate on the bone marrow stroma. We plan to establish a co-culture of ALL cells with 3D cultured bone marrow Mesenchymal Stroma Cells (BM-MSCs), as published by Sieber et al. (2017). For that, a hydroxyapatit coated zirconium oxide ceramic is seeded with patient derived MSCs and ALL cells to mimic the in vivo conditions. The whole cultivation is performed dynamically in the "Multi-Organ-Chip" (MOC). The MOC-platform, which has been developed at the chair of Medical Biotechnology at Technical University, is a microfluidic device consisting of a circular channel system which connects wells for the culture of different small functional human organ units, called organoids. Currently used 2D stroma cultures fail in their ability to support primary ALL cell proliferation and are therefore limited to test regenerative potentials of MSC cultures. This minimized model of ALL could be used for drug testing and dosage estimation. The in vitro leukemia model would present a breakthrough for detailed studies of the human marrow and for personalized drug screenings.

Team: Kübrah Keskin, Tessa-Lara Skroblyn, Domenic Schlauch, Cornelia Eckert, Mark Rosowsky

Funding: Einstein Kickbox - Young Scientists

Linking functional outcomes with regenerative potential: Can ultrasonography identify biomarkers of early healing and long-term recovery in human Achilles tendon rupture?

The ability to walk independently and pain free directly affects mobility and quality of life1,2. An essential function involved in walking is foot plantarflexion, articulated by a muscle-tendon unit containing the Achilles tendon (AT). Acute injury, like Achilles tendon rupture (ATR), leads to lowered strength and long-term functional outcomes3–5 regardless of treatment6, and puts patients at a higher risk for further injury7,8. The incomplete regeneration of the AT is the main contributor to functional deficits9, yet few studies have directly investigated regenerative capacity with function.

The possibility to utilize biomarkers to predict tendon healing has been suggested but requires further investigation for validation. After ATR, late surgical intervention leads to an imbalance in tendon homeostasis that is time-dependent10, but has yet to be related with AT function.

Properties of the healed tissue are difficult to characterize in vivo. One available method measures AT length changes using ultrasonography during active muscle function11. The AT’s capacity to store and transfer forces is due to its compliance, which allows muscle efficiency12; following ATR, this capacity is diminished.

This research aims to link the AT’s intrinsic regenerative capacity at the time of surgery with resultant healed AT tissue function. Our goal is to identify markers predictive of human ATR healing outcomes by combining investigations of early healing events with late-stage tissue function.

Tearm: Alison Agres, Kirsten legerlotz, Britt Wildemann, Sebastian Manegold

Funding: Einstein Kickbox - Young Scientists

Einstein Kickbox Projects - Förderperiode 2017

Fighting liver cirrhosis? Establishment and analysis of decellularized human cirrhotic liver slices as a 3-dimensional model to study cell matrix interactions

Liver cirrhosis is one of the main indications for liver transplantation. Due to the organ shortage, this therapy option is limited to the minority of patients suffering from cirrhosis. Therefore, there is a need of alternative treatment options.The aim of our project is to establish a decellularization protocol for human cirrhotic livers slices, which preserves the natural extracellular matrix (ECM) of cirrhotic livers. These decellularized liver slices will serve as a 3 dimensional model to study cell matrix interactions. If we are able to establish a protocol which will preserve the ECM, we will conduct in vitro recellularization experiments to study how the cirrhotic ECM will change the genotype and phenotype of different cell types. With this knowledge we aim to modify specific cell types in vivo or vitro for example prior to cell transplantation. Our ambition is to steer the cell matrix interaction via these modified cells after their transplantation and thereby halt or even reverse the progress of liver cirrhosis. This approach may offer an alternative treatment option in the future.

Team: Karl Hildebrandt, Oliver Klein, Igor Sauer    

Funding Scheme: Kickbox

In need for neuroregeneration ! - Development of a novel targeted drug for stroke treatment beyond the time window of thrombolysis

After stroke, the brain can compensate for lost neuronal tissue functions by rewiring of the neuronal network. However, in adult brains, post-ischemic healing is compromised, since neuroplasticity is limited by the adult shape of ECM consisting of a very dense meshwork of ECM proteins. We have shown, that endothelial cells can steer the post ischemic ECM remodeling depending on the inflammatory Stat3 pathway (Hoffmann et al., 2015). In this project, we want to shape the inflammatory endothelial cell response after stroke using a targeted drug for endothelial Stat3 activation. This will steer the remodeling of the ECM towards a neuroplasticity permissive status. This might help to overcome the compromised healing and regeneration after stroke. We will evaluate the drug in mice using a transient filamentous occlusion of the middle cerebral artery (MCAo) as stroke model and behavioral tests to determine effects on long-term functional outcome. We will monitor regenerative effects by visualization of neuronal network changes by viral and chemical tracing techniques as well as DTI and resting state MRI sequences. ECM remodeling will be determined histologically with an emphasis on the perineuronal net and CNS Ranvier´s node ECM.    

TeamChristian Hoffmann, Christoph Harms, Gisela Lättig, Philipp Böhm-Sturm

Funding Scheme: Kickbox

BMPingECM– BMP/TGFβ regulation within the extracellular matrix: From rare disease cellular models to altered ECM and cell- mechanics

The extracellular matrix (ECM) instructs cells to orchestrate crucial aspects of their biological behavior. As a multidisciplinary team of cell biologists, biochemists and biophysicists we set out to investigate biophysical and biochemical features of the ECM from endothelial cells with different signalling backgrounds and found striking changes in its composition and growth factor reservoir capacity. We uncovered feedback regulations affecting transcriptional responses, adaptations of the cytoskeleton and the ECM and altered mechanical properties explaining the vicious cycle in the development of vascular diseases.

The ECRT support enables us to characterize these biochemical and biophysical characteristics of the altered ECM with unprecedented resolution and to provide new mechanisms that potentially help to understand the involvement of BMPs and TGFb in successful and failing endogenous repair scenarios.

Team: Christian Hiepen, Petra Knaus, Kerstin Blank, Peter Fratzl

Funding Scheme: Kickbox

How do cellular dynamics shape vascular network structure?

Angiogenesis is a fundamental process in development, cancer, and regeneration. Complex signaling pathways regulate tip selection, tip migration, and stalk cell proliferation to shape the emerging vascular network. To improve our basic understanding of how signaling interactions within individual cells determine vascular network architecture, we need multi-scale computational models that integrate the cellular signaling dynamics into tissue level dynamics. In the kickbox phase, we will implement the software necessary to efficiently simulate intracellular dynamics in multi scale agent based models and generate a proof of concept study.In the follow up project, we aim to collaborate with experimental scientists to iteratively generate, test, and refine hypotheses on how intracellular signalling defines vascular network structure.

Team: Clemens Kühn, Judith Wodke, Sara Checa Esteban, Edda Klipp, Georg Duda

Fundind Scheme: Kickbox

Uncover the Role of IL-4 in Hyaline Cartilage Homeostasis and Osteoarthritis

The objective of the project is to uncover the function of IL-4 in cartilage homeostasis with available murine and human material applying different methods. Furthermore, we will work on a concept to implement in silico methods as a strong tool to study biological processes and signalling pathways and to use the power of an interdisciplinary collaboration towards a common goal. In a following (advanced) project, we aim to clarify the role of IL-4 in the pathogenesis of OA, to provide evidence-based approaches on how to overcome these compromised conditions and to identify new therapeutic targets towards OA to challenge an unmet clinical need that has remained unresolved for far too long. 

Team: Annemarie Lang, Katharina Schmidt-Bleek, Max Löhning, Susanna Röblitz, Frank Buttgereit

Funding Scheme: Kickbox

Quantifying the quadricep force in exercise mediated osteoarthritis therapies

Our project is aimed to prototype new mathematical models which explain the forces produced by the quadricep in exercise meditated OA therapies. We wish to extend existing isometric quadricep models to general motions by enriching the equations using prosthesis data. We are looking for groups working in biomechanics and focused on quantifying qualitatively the effects of exercise mediated therapies.

TeamVikram Sunkara, Max Von Kleist, Georg Bergmann

Funding Sceme: Kickbox

The Role of T-cell Activation Levels in Periprosthetic Joint Infection Development

With increasing life expectancy and concurrent high demands regarding personal mobility, the numbers of total joint arthroplasties (TJA) are rising. Accordingly, larger numbers of infections are documented. Periprosthetic Joint Infections (PJIs) account for the majority of implant failure, occurring in 2- 3% of all primary TJAs with even higher rates of 3-10% in revision surgeries. A consistent diagnostic after TJA is critical for the therapeutic success. Particularly the diagnostics of persistent low grade infections is still insufficient, calling for the development of highly sensitive diagnostic tools for early detection.

Immunologically reactive molecules are released from T-cells upon cell activation. We hypothesize that selected molecules can not only be used to assess the level of T-cell activation and the reactivity of the adaptive immune response, but also as a marker for lingering infections. Furthermore, their level may serve to clarify an underlying molecular predisposition for endogenous infection management and potentially even resume a protective role in infections.

Defining a biomarker on protein level, that enables local, minimally invasive and reliable diagnostics in the field of PJI while giving insight into the patients’ general immune status, is an ambitious, novel and innovative approach.

The project elements for the KickBoxSeed-Grant are in the focus area of “cellular mechanisms in compromised healing” while the long-term vision of the project additionally addresses the local modulation of inflammation. The concept provides an interface between cell-based immunology and pathogen-based infectiology/immunology with endoprosthetic infections as a clinically highly relevant field of application.

Team: Andrea Sass, Michael Fuchs, Simon Reinke, Anke Dienelt, Janine Mikutta, Andrej Trampuz, Carsten Perka, Juri Rappsilber

Funding Scheme: Kickbox