Investigation of the regulation of neural progenitor cells in the human developing neocortex

Dr. Mareike Albert, TU Dresden, CRTD
Dr. Katie Long, King‘s College, IoPPN

The human neocortex is the seat of many of our higher cognitive functions and has undergone a dramatic expansion during evolution. However, how this expansion occurred is still not fully understood. The extracellular matrix may have contributed to neocortex evolution as it has already been shown to i) regulate the proliferation of neural progenitor cells and ii) be more highly expressed in the developing human neocortex than in the mouse.

This research project will focus on the extracellular matrix components found to be expressed in the human but whose expression is epigenetically inhibited in the developing mouse neocortex. The project will be carried out in collaboration with the “Development of human neocortex” group let by Dr. Katie Long at King’s College London.

Together, our labs will investigate the function of these extracellular matrix components in human neocortex development by infibiting their function in human fetal neocortex explants. The collaboration will involve research visits from a PhD student from the Dresden International PhD Program to King’s College as well as visit from Dr. Long to TUD. Research findings published as the result of this new collaboration will form the basis for future joint third-party funding applications.

Research Workshops: Finite-and infinite-dimensional Lévy-type processes

Prof. Dr. Anita Behme, Prof. Dr. René Schilling, TU Dresden, Faculty of Mathematics
Prof. Dr. Markus Riedle, Prof. Dr. Eugene Shargorodsky, King’s College London, Faculty of Mathematical and Natural Sciences

Together with their colleagues Anita Behme and René Schilling (TUD), Markus Riedle and Eugene Shargorodsky (King’s), as new appointed transCampus Professors in Mathematics, are planning to set up a series of joint research projects to supervise PhD students and to establish joint teaching modules. In this project, two intensive workshops of two days each will take place in December 2020 at the TUD and in September 2021 at King’s, as a part of one week group meetings (Behme/Schilling/Riedle/Shargorodsky).

Lévy- and Lévy-type processes form important classes of stochastic processes for the modelling of various real-world phenomena where jumps in the observed quantities can occur (i.e. stock prices, workload processes, sub- and super-diffusion in biological or chemical systems). The interaction of analysis and probability theory is fundamental to describe 1) the existence, 2) the uniqueness, and 3) the stochastic properties of the observed processes. The objective of this joint research project and the workshops is to investigate the points 1-3 for infinite dimensions. This is especially relevant for a better understanding of stochastic large-scale systems.

The workshops aim at enhancing the scientific exchange, i.e. the exchange of the latest research results and the initiation of new collaboration projects (open problem sessions). Moreover, the workshops are intended to promote young scientists, e.g. with the forum for PhD students and early-career scientists. In particular, PhD students from King’s and TUD will be given the opportunity to visit the partner institution and to establish their own contacts. Therefore, the project team will invite other colleagues from King’s and TUD, as well as colleagues from Wroclaw, to join the existing cooperation. This will increase the international visibility of the transCampus initiative and put the cooperation in a broader context.

International Reseach Group on "Wellbeing and Resilience Competency Development"

Prof. Dr. Bärbel Fürstenau, TU Dresden, Faculty of Business and Economics
Dr. Patricia A. Zunszain, Dr. Juliet Foster, King’s, IoPPN

Project coordination and contact:
Ianina Scheuch, TU Dresden
Dr. Gisele Dias, King's

The project aims to establish an international interdisciplinary collaboration between Technische Universität Dresden (TUD) and King's College London (KCL) on the topics of wellbeing and resilience competency development. Our project’s goals are two-fold: to provide in-depth research-based insights into the development of resilience as a competency for current and future professionals and to adapt and develop novel learning approaches that can be used as interventions to promote and enhance both competency and wellbeing among different students of different subjects and in different settings (e.g., face to face and online settings).  In this sense, we aim to bridge research on education, learning, psychology and neuroscience to strengthen our interdisciplinary research cooperation and to provide young researchers and students with opportunities for exchange in both academia and research.

Our project will commence with research on implementing a collaborative teaching programme focused on developing competency in resilience and wellbeing. Due to current challenges and social distancing urged by COVID-19, our partner at KCL designed a novel online coaching programme, titled “Time to Thrive”, which we plan to offer to university students at TUD. The project’s results will be examined and evaluated by the international research group, including students in both institutions. The research group also plans to enhance cooperation on additional related topics with other partners within our universities.

A joint teaching and network initiative on "Transcultural Adaption"

PD Dr. Wieland Schwanebeck, TU Dresden, Institute of Anglistics
Dr. Ian Smith, King's college, Film studies

A transcultural approach to the field of adaptation studies offers the discipline a chance to reconceptualise itself beyond the classical dichotomies of ‘original’ and ‘adaptation’ and, by implication, of ‘us’ vs. ‘them’. The idea of transculturalism goes beyond old-fashioned ideas about monolithic cultures and is thus wholly appropriate to the contemporary globalised world.

It is the aim of this project to go beyond existing forays into transcultural adaptation, for these are usually limited to studying traditional forms of ‘adaptive traffic’. By contrast, this project will not only put a distinct emphasis on methodological groundwork and explore hotly debated topics like border-crossings, hybridity, and appropriation, it will also ponder adaptation beyond the traditional literature/film divide by considering contemporary phenomena like the narratives of migration, and adaptation in the digital age.

To do justice to the complex field of transcultural adaptation studies, we are proposing a project with three central components: 1) a joint teaching initiative that will introduce students to basics of transcultural adaptation studies and the field of world cinema, as well as to hotly contested current debates, like cultural appropriation; 2) an international workshop which will continue the groundwork which was laid in 2018 with a workshop in Dresden; 3) a network project, which has the explicit aim of prepping a joint publication: a textbook introduction to the field of transcultural adaptation studies which will survey existing and heavily contested concepts like adaptation-as-colonisation and appropriation.

Online study: Resilience and well-being of entrepreneurs through the COVID-19 pandemic

Dr. Dominika Wach, TU Dresden, Facolty of Psychology
Prof. Dr. Ute Stephan, King’s college, School of Business

As the COVID-19 pandemic unfolds and is being contained, the slide in stock markets in the US, Europe and Asia have grabbed the headlines, but less attention is given to the entrepreneurs who are leading the numerous firms that make up the backbone of our economies and provide most jobs (Eurostat, 2018). Indeed, we know very little about the resilience and well-being of entrepreneurs confronted with the crises.

Thus, our first aim is to understand what challenges entrepreneurs face through a crisis such as COVID-19 and how this crisis affects their individual and business well-being, creativity and performance. Our second aim is to understand which individual and business-related factors helped entrepreneurs to be resilient and positively overcome that crisis. Finally, our third aim is to understand whether and how different contexts across 22 countries (political strategies and social welfare systems) enable or constrain entrepreneurs’ resilience in the face of the COVID-19 crisis. This will enable us to derive new theoretical insights, as well as relevant policy recommendations about how to support entrepreneurs’ resilience in crises.

To address our research questions, we will conduct a longitudinal online study in which are going to look at resources, strategies, psychological capital, and recovery as explanatory mechanisms to maintain entrepreneurs' personal well-being and recover their businesses. To extend our knowledge about how resilience unfolds over time and what decision-making dynamics in time of crisis are, we planned additional 40 in-depth interviews.

For further information on the global study of entrepreneurs' well-being please visit the King's College London website.

Study on the Transcription Factors in the Regenerating Zebrafish fin

Jun.-Prof. Dr. Franziska Knopf, TU Dresden, CRTD
Prof. Dr. Jeremy Green, King’s college, Faculty of Dentistry, Oral & Cranofacial Sciences

The zebrafish has been widely studied regarding its regeneration, because it restores organs that poorly regenerate in mammals. Among the tissues and organs that are studied are the spinal cord, retina, heart, kidney, and caudal fin. Fins, which contain bone, are replaced within a short time via a process called epimorphic regeneration. Restoration of tissue function requires appropriate growth and patterning processes.

While previous studies have underlined the importance of individual signaling pathways, we will use a more comprehensive approach to visualize the impact of downstream transcription factor networks as executive players of regeneration. To do so, we will use the transCampus seed funding to determine the localization of transcription factors in the tissue and to analyze existing gene expression data. 

We will discuss mathematical models on the impact of these networks on tissue boundary formation in the regenerate with Prof. Jeremy Green, who is an expert in modeling patterning processes in the mammalian craniofacial skeleton. Our preliminary data will then be used to draft a research grant proposal, which paves the way for investigation of key interactions within a rapidly regenerating vertebrate appendage.

Imaging and electrophysiological response markers to ketamine treatment in bipolar depression

Dr. med. Philipp Ritter, TU Dresden, Faculty of Medicine
Prof. Dr. Allan Young, Prof. Dr. Anthony Cleare, King’s college, IoPPN

While the neurobiological mechanisms of antidepressant response to the fast acting N-methyl-D-aspartate (NMDA) receptor antagonist ketamine has received substantial attention during the past years, there has been very limited research on bipolar depression.

The aim of the project will be to establish a working collaborative infrastructure and cross-campus PhD for multimodal functional neuroimaging (EEG & resting state fMRI) between the Centre for Neuroimaging Sciences at the IoPPN and the Department of Psychiatry and Psychotherapy in Dresden. Building on previous exchanges and reciprocal lectures regarding the use of novel, rapid acting antidepressants (ketamine & psilocybin) we will aim to establish common research protocols to provide the basis for the investigation of response markers and mechanisms in bipolar depression.

The TUD site has developed clinical expertise in the use of ketamine for the treatment of bipolar depression but the research parameters of interest have been limited to toxicity markers and psychopathology. The substantial expertise in multimodal functional neuroimaging at the IoPPN (KCL) will provide the basis for a comprehensive and both spatially and temporally highly granular investigation into potential neurobiological response markers and mechanisms.

Once feasibility has been established we aim to initiate a joint cross-campus PhD for the investigation of response markers and mechanisms of rapid acting antidepressants.

Diabetes and prostate cancer: Characterization of the membrane-bound androgen receptor ZIP9

Sen-Prof. Dr. Günter Vollmer, TU Dresden, Faculty of Biology
Prof. Dr. Christer Hogstrand, King’s college, Faculty of Life Science and Medicine

The objective of this project is to explain the role of the membrane-bound androgen receptor ZIP9 in pancreatic cells in the context of diabetes and in prostate cells in the context of prostate cancer. In order to understand the function of the gene ZIP9 in both organ systems, its function in both cell lines representing the two organ systems will be deactivated. This will be done using the CRISPR/Cas9 method.

In both participating research groups either the functional knock-outs have already been performed (KCL) or the corresponding methods for functional knock-out have been established (TUD). The aim of the current works is to functionally characterize cells with a zero mutated ZIP9 gene.

The cell line Min6 from islet cells of the pancreas (KCL) and the prostate carcinoma cell line PC3 (King’s) serve as experimental models that link the project to the existing International Research Training Group 2251 between the Medical Faculty of TU Dresden and King’s College London and to other transCampus research activities. Young scientists will be involved in the scientific work, which is realised at both partner institutions, for example by writing a master thesis. Publishing the results of this preliminary study will allow the research group to apply for a public grant for a follow-up research project.

Metabolic profiling of the stromal bone marrow compartment in acute myeloid leukaemia (AML)

PD Dr. Manja Wobus, TU Dresden, Faculty of Medicine
Prof. Dr. Eric So, King’s college, Cancer centre

Acute myeloid leukaemia (AML) is the most common acute leukaemia in adults. It is a haematological malignancy arising from the occurrence of genetic mutations in clonal hematopoietic progenitors, which cause a block in differentiation and an uncontrolled growth of leukemic blasts in the bone marrow. Beside direct targeting the leukemic cells other approaches aim to identify and target common features within this complex disease. One potential target is the bone marrow microenvironment, which is the site where leukemic cells arise, expand, and eventually develop resistance to therapy. It is constituted out of different types of cells, e.g. mesenchymal stromal cells (MSCs), with a predominant vascular component responsible for nutrient and metabolite turnover, the ingress and egress of different cells, and the regulation of normal hematopoietic stem and progenitor cell (HSPC) function. Thus far, comprehensive analyses of the molecular and metabolic changes in AML BM MSCs of larger patient cohorts are sparse.

Therefore, we will apply our expertise on MSC biology for investigations of metabolic changes in distinct types of AML, such as MLL- and NPM1c-AML. Our collaboration partner at King’s, Prof. Eric So, will analyze molecular mechanisms of chemoresistance and leukemic stem cell activity in these AML subtypes using single cell multi-omics approaches.

We aim to analyze serial samples (diagnosis/remission/relapse) from 5-10 MLL-AML and NPM1c-AML patients. The samples and the respective clinical data are collected within the scope of the AML registry of the German-wide “Study Alliance for Leukaemia” (www.sal-aml.org) coordinated in Dresden. While the cellular heterogeneity and key molecular features of AML cells will be analyzed by our King’s partner, Professor So, the stromal fraction will be 1. directly analyzed at the Metabolomics-Platform of the NCT and processed for RNA sequencing and 2. MSCs will be further cultured and analyzed.

The overall goal is a better prediction of treatment response of distinct AML cases and therefore potentially a more host- and disease-specific therapeutic intervention.

Interaction of SOX2 with HIF-MYC/MAX complex and subsequent impact on phenotypic features of tumours in the adrenal glands

Dr. Nicole Bechmann, Prof. Ben Wielockx, TU Dresden, Faculty of Medicine
Dr. Cynthia Andoniadou, King’s college, Faculty of Dentistry, Oral & Craniofacial Sciences

Phaeochromocytomas and paragangliomas (PPGLs) are catecholamine-producing tumours in the adrenal glands with distinguished phenotypic features. Pseudohypoxic cluster 1 PPGLs are characterised by an activation of hypoxia-pathways mainly due to an increased expression and stabilisation of hypoxia inducible factor (HIF) 2α and show an undifferentiated phenotype (immature catecholamines), while cluster 2 PPGLs exhibit a differentiated phenotype.

Our previous work suggests that the interaction of HIFs with the MYC/MAX complex play a significant role in this regard. Furthermore, the work of Das et al. (2019) indicates that the transcription factor SOX2 may also influence the interaction between HIF2α and MYC, thereby regulating cell differentiation and self-renewal. Therefore, we hypothesised that SOX2 interacts with the HIF-MYC/MAX complex and thereby substantially contributes to the regulation of phenotypic features in PPGLs.

Initially, tumour and normal adrenal tissue of PPGL patients will be examined with regard to the co-expression of SOX2, HIF2, MYC and MAX (immunohistochemistry) and subsequently the expression will be correlated with differentiation markers such as PNMT. Available mouse strains will allow manipulation of Hif2α (Prof. Wielockx, TUD/MF) in Sox2 cells (Dr. Andoniadou, King’s) and help elucidate our understanding of underlying mechanisms. State-of-the-art technology for genetic manipulation will be applied to regulate the expression of Myc and Sox2 in mouse phaeochromocytoma cells in the presence or absence of Hif2α expression.

It is expected that the proposed project will contribute significantly to our understanding of the molecular mechanisms involved in the regulation of phenotypic characteristics in PPGLs. This may lead to the identification of novel therapeutic strategies to improve the outcome of these patients. Within the framework of this project, the basis for a joint project application will be generated.

Antonio Galleu (King's, Stem Cells & Regenerative Medicine) & Martin Bornhäuser (TUD, Faculty of Medicine, Internal Medicine I)

Mesenchymal Stromal Cells (MSCs) represent an attractive treatment for patients with steroid refractory acute Graft versus Host Disease (GvHD) after allogeneic Haematopoietic Stem Cells Transplantation (HSCT). However, a significant proportion of patients do not respond, and no effective treatments are available. The pressing urgency of implementing new therapies for these patients is still an unmet need.

To improve the clinical outcome of these patients, we propose to characterize the potency of different MSC preparations in order to select those with the highest therapeutic activity. However, responses to MSCs are rather unpredictable and this is largely the consequence of a heterogeneous cell preparation.

We have recently discovered that the therapeutic activity of MSCs depends on their ability to undergo in vivo apoptosis and consequently to reprogram inflammation via re-educating monocytes/macrophages towards an immunosuppressive phenotype. This discovery provides a new mechanistic angle to classify MSCs based on their therapeutic potential. Our hypothesis is that the susceptibility to undergo apoptosis and induce immunosuppressive macrophage polarization offers a criterion to select clinical MSC batches.

The results will not only be invaluable in assisting MSC based therapies but also to better understand the heterogeneity of MSC populations. The outcomes will have an invaluable impact on the manufacturing protocols of MSCs, since we will be able to classify any MSC preparation and identify MSCs with the most potent therapeutic profiles by selecting the best donor and cell source. This ultimately will translate into a better management of GvHD, with the possibility to extend the indication of curative allogeneic HSCT to most patients with leukaemia.

Dr. Anthony Vernon (King's, Basic and Clinical Neuroscience)
Prof. Gerd Kempermann (TUD, Faculty of Medicine, DZNE)

As medicine acknowledges inter-individual differences as a key determinant in diagnosis and treatment, understanding the biological mechanisms underlying individuality becomes increasingly important. However, underlying mechanisms at the levels of cells, tissues, systems or the entire brain and their interaction across these scales cannot be determined in human subjects because it is not possible to collect all relevant phenotypes with sufficient depth and precision or to manipulate the processes in question experimentally. Thus, addressing these problems calls for a suitable animal model in which both environment and genotype can be strictly controlled.

In this application, we will use the synergy the transCampus initiative has already created between the Kempermann (TU Dresden) and Vernon Labs (KCL) on the macro scale effects of exposure to an enriched environment using MRI, to ask new questions regarding the neurobiology of inter-individual differences. Specifically, we will test the requirement for adult hippocampal neurogenesis (AHN) in the emergence of individuality phenotypes at the level of the brain using magnetic resonance imaging (MRI) and behaviour in populations of isogenic mice following exposure to an enriched environment (ENR).

We have undertaken together one small proof-of-concept study that is in preparation for publication. The proposed extended pilot study builds upon that initial work and will deliver (1) one potential cellular mechanistic explanation for individualization and (2) cross-species MR imaging biomarkers for future longitudinal MRI studies in mice and forward translation to humans. Our collaboration sets out to develop a translational research program that aims at developing sound neurobiological foundations of lifestyle-dependent risk and resilience and identifying biomarkers with high predictive value.

Dr. Ismael Diez Perez (King's, Pyhsical Chemistry)
Gianaurelio Cuniberti (TUD, Material Sciences and Nanotechnology)

The Chirality-Induced Spin Selectivity (CISS) has recently emerged as a powerful alternative to ease the design of nanoscale spintronic devices. The intrinsic room-temperature spin-polarization power of a chiral molecular structure allows one to manipulate and control spintronic interfaces without the need for a permanent magnet, which significantly simplifies the device design. Beyond applications, the fundamental understanding of CISS extends all the way to biology, bringing explanations to outstandingly efficient biological processes such as biorecognition or long-range charge diffusion.

The present King’s College-TUD consortium aims for a comprehensive study of the spintronic details of a chiral molecule/electrode interface as function of key experimental parameters determining its spin-polarization performance, namely, intrinsic molecular dipole, molecular length, electrode/molecule coupling strength and electrode material. Comprehensively measuring all these variables in the exact same system will directly place us in position to, first, fully understand the physical basis of a CISS-based molecule/electrode interface, and second, configure a much desired list of design principles for future CISS-based spintronic devices.

The concepts learnt here will also help boost understanding the role of homochiral motifs recurrently exploited in biological systems in topics such as local magnetic fields affecting enzymatic reactivity and/or the possible role of spin-polarized currents in the long-range electron transfer/transport in biology.

Prof. Dr. Benedikt Berninger (King's, Developmental Neurobiology)
Dr. Tomohisa Toda (TUD, Faculty of Medicine, DZNE)

Direct reprogramming of cell identity across cell lineages, such as of glia into neurons, emerges as a novel cell-based strategy for brain repair. Every cell type exhibits a characteristic nuclear architecture that goes hand-in-hand with 3D genome organisation and gene expression.

Here we pursue the hypothesis that nuclear remodelling is quintessential for reprogramming of cell fate. Evidence from the Toda lab (TUD) shows that the nuclear pore protein nucleoporin 153 (Nup153) plays a key role in neural stem cell maintenance. Using in vitro and in vivo models of glia-to-neuron conversion, developed by the Berninger lab (KCL), both partners wish to explore the role of Nup153 and other nuclear structural proteins in reprogramming of glia into neurons. Towards this, we will employ our complementary expertise in super-resolution microscopy, epigenetic essays to probe for interactions between nuclear pore proteins and reprogramming factors, and functional gain- and loss-of-function studies of Nup153 in cultures of mouse primary astrocytes as well as the postnatal cortex in vivo.

We believe this study will lead to ground-breaking discoveries regarding the importance of nuclear architecture remodelling during cell fate conversion and pave the way for improved reprogramming strategies for brain repair. Our observations may not be restricted to the central nervous system, but are likely to be valid for other organs and tissues as well, such as pancreas and heart.