The Kickbox project proposals that were granted kickbox seed funding for the period April-October 2017 are listed below:

Decoding the aged matrix - consequences of cellular senescence for tissue patterning and stem cell invasion

Bone fractures are one of the most frequent orthopedic problems requiring medical treatment. Facing an aging population, specifically in the western world, a better understanding of how bone regeneration processes are altered with age is essential to develop novel treatment strategies satisfying the clinical need. We have recently developed a toolbox to simulate and study extracellular matrix (ECM) formation in vitro by cultivating primary human fibroblasts inside 3D macroporous collagen scaffolds. We propose that under compromised conditions such as aging, these early tissue formation processes are altered (e.g. by ECM secretion pattern, ROS level, cellular tension) with further consequences for stem- and progenitor cell migration, proliferation and differentiation.

Team : Erik Brauer, Sophie Schreivogel, Daniela Mau, Uwe Kornak, Ansgar Petersen

Team message : Motivated master students willing to perform their thesis or an internship within this interdisciplinary field of biomechanics, biomaterials, genetics and tissue engineering are mostly welcome to contact us.

Contact : erik.brauer@charite.de

Creating a nephro-vascular unit ex-vivo from human pluripotent stem cells.

Our project deals with fostering human pluripotent stem cell (hPSC)-derived renal organoids into mini-kidneys. We are trying to encourage intercellular interactions, growth and morphogenesis within the organoid by providing the chorio-allantoic membrane (CAM) of chick embryos as a vascular niche for ectopic organogenesis. This experiment will help us estimate the degree of maturation of the organoid into an organ upon introduction of oxygen supply and shear flow. The results of this experiment will be used to tailor a 3D-printed, chip-based perfusion system to mimic the nephro-vascular unit that developed from a fetal to an adult stage on the CAM. This chip design will be realized using flexible funds and can be used as an ex-vivo culture system for healthy and patient-derived induced kidney cells.

Team : Krithika Hariharan, Su-Jun Oh, Andreas Kurtz  

Team message : We are seeking collaboration partners for imaging and chip-based technologies.

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 Hillebrandt, Oliver Klein, Igor Sauer    

Team message : We are interested in collaborations with experts in the field of molecular mechanism in liver cirrhosis. 

ContactKarl-herbert.hillebrandt@charite.de

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.    

Team : Christian Hoffmann, Christoph Harms, Gisela Lättig, Philipp Böhm-Sturm

Contact : christian.hoffmann@charite.de

 

Regenerative potential of adipose tissue - Unraveling the crosstalk between adipocytes and hypertrophic scar tissue

Our project is based on observations from plastic surgery: autologous fat grafts lead to a significant reduction of scar tissue. We will attempt to identify the fat components responsible for this phenomenon, as well as the molecular pathways they work within. Therefore, we will study the interactions between myofibroblasts, a cell type already known to play a crucial role in wound healing, adipocytes and the adipocyte secretome. Since wound healing processes include changes to the extracellular matrix, we will analyze matrix remodeling alongside changes to the intracellular signaling of myofibroblasts cultured in 2D and 3D. Ideally, we would like to incorporate a pathological phenotype into our studies. To this end, a research stay in the group of Susan Gibbs, Vrije University Amsterdam, has been organized during the Kickbox period, during which we will work with fibroblasts isolated from hypertrophic scars. 

Team : Katharina Hörst, Uwe von Fritschen, Nan Ma, Susan Gibbs, Sarah Hedtrich

Team message : We are seeking collaboration partners working with scar tissue/fibrosis models as well as partners for the analysis of the adipocyte secretome. We also offer the possibility for master students to do their thesis in our lab. 

Contact : katharina.hoerst@fu-berlin.de

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

Team message: We seek collaboration partners for a combined experimental/modeling project on signaling in angiogenesis. We also seek motivated Master’s students for the kickbox project.

Contact: clemens.kuehn@charite.de

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

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

Team message: We are seeking collaboration partners for biomechanical studies.

Contact: annemarie.lang@charite.de

Role of mechanics and tissue architecture in pancreatic cancer and post-operative complications

Team: Evi Lippens, Rosa Schmuck, Amaia Cipitria, Dag Wulsten, Daniela Garske

 

Contact: evi.lippens@charite.de

Urinary stem cells as biomarkers for kidney damage and endogenous repair capacities

Our project aim to establish urinary stem cells as a biomarker for the prediction of renal recovery in patients suffering from acute kidney injury (AKI). AKI is one of the most frequent causes of renal function. While some of the patients show at least some degree of recovery, up to 30% show a permanent loss of their renal function. Presently the driving force of recovery is unknown. We hypothesize that the cell composition in urine mimics the structural damage and regenerative potency of the injured organ and predict that increased amounts of kidney - detached stem cells in urine herald recovery, while their absence indicate permanent damage. The correlation of the total number of renal stem cells in the urine will not only help to predict renal recovery, it will additionally allow direct monitoring of renal regeneration and thus, provide a surrogate marker for clinical studies.

Team: Bella Roßbach, Philip Enghard, Khadija El-Amrani

Contact: bella.rossbach@charite.de ,Philipp.enghard@charite.de

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.

Team: Vikram Sunkara, Max Von Kleist, Georg Bergmann

Team message: We´d like to hire two students, one from biophysics and one from informatics to help prototype our new models.

 Contact: sunkara@mi.fu-berlin.de

Designing novel drugs for balancing the inflammatory phase - A mathematical approach

Recent research has shown, that a balance between suppression of inflammation and hyper-inflammation is crucial for regeneration and wound healing. Inflammation is often accompanied with tissue acidosis. This results in a different chemical environment of the pathogene (low pH) versus the healthy tissue (normal pH). We develop a novel method to keep the inflammation balanced by drug therapy. For this purpose, a drug is needed which has an activity controlled by the chemical environment. In this context an efficient drug to shape the inflammatory phase should act in hyper-inflamed regions and be almost inactive in low inflammatory parts.

In cooperation with Charité we already developed a selective opioid which only acts in inflamed tissue. The corresponding mathematical models and tools will be transferred to the regenerative therapy context. For understanding how to shape the inflammatory phase of regeneration we employ mathematical modeling. Our methods allow for modeling molecular systems in balance can map the relevant processes in dependence of the inflammatory state.

Team: Marcus Weber, Konstantin Fackeldey, Christoff Schütte

Contact: weber@zib.de

 

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

Contact: Andrea Sass

 

Thyrospheres – An hiPSC-derived Thyroid-Follicle-Model for Basic and Translational Science

The thyroid is one of the most affected organs when it comes endocrine pathologies. It is a perfectly build reactor-like system within our body to deliver the needed amounts of thyroid hormone to regulate fetal development or e.g. energy metabolism later in life. Thyroid hormone synthesis happens in a tightly regulated and well-balanced system with feedback inhibition and crosstalk to various other hormonal systems.

To test scientific paradigms and hypothesis, there are limited options especially in the field of in vitro test systems. The structure of the thyroid gland, and especially its substructure unit, the follicle, can’t be copied by a simple monolayer cell culture, as its function prerequisites a lumen, surrounded by a monolayer of specialized cells, the thyrocytes. Just within this lumen, our organism is able to synthesize thyroid hormone.

Therefore novel 3D cell culture models are needed.

 

The aim of our project is to generate a human 3D organoid model that replicates the tissue architecture including follicles of the thyroid. We will use human induced pluripotent stem cells (hiPSC) to differentiate towards thyroid. To archive this we will utilize factors and manipulate signaling pathways known to play a role in thyroid development in the embryo. These factors will be used for screening e.g. their dosage, combination, sequential application and application time to drive the hiPSC towards thyroid. 

 

Team: Kostja Renko, Harald Stachelscheid, Özlem Vural, Roland Lauster, Manfred Gossen

Contact: Renko, Kostja


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