The neocortex controls humans most distinguishing cognitive functions; yet, we are just beginning to unravel the mechanisms that control neural progenitor cell behavior during human neocortex development. Epigenetic mechanisms are essential for the precise regulation of gene expression patterns. Here, we propose to analyze the dynamic patterns of epigenetic modifications in human neural progenitor cells at different stages of neurogenesis. In particular, we will focus on a key human neural progenitor cell type, called basal radial glia, which is rare in the mouse but abundant in human. This project will combine the expertise of Dr. Long's group (KCL) in human neurogenesis and Dr. Albert's group (TUD) in the epigenetic regulation of gene expression. The project will include research visits from PhD students, providing training opportunities in advanced neuroscience methods that the two groups have established. This new project aims to generate epigenetic reference data sets that are expected to provide a firm basis for joint publications and third-party funding applications, representing a milestone in the further development of the collaborative effort between the two groups.

Completely funded.

Pheochromocytomas and paragangliomas (PPGLs) are catecholamine-secreting tumors characterized by variable disease aggressiveness [1]. In particular, PPGLs with mutations in succinate dehydrogenase subunit B (SDHB) are associated with increased risk of developing metastases. We previously demonstrated that increased expression and stabilization of HIF2α contributes to metastatic processes in these tumors [2].

Nevertheless, we have not yet fully understood why tumors with mutations in SDHB are more aggressive compared to other PPGLs that are also characterized by increased HIF2α expression. The involvement of intra-tumor heterogeneity in metastasis has already been shown in other tumor entities, but PPGLs are largely unexplored in this area. Therefore, we aim to investigate the crosstalk between different tumor cell subpopulations (HIF2α-driven vs. non-HIF2α-driven cells and SDHB-driven cells vs. non-SDHB-driven cells), and how this crosstalk affects tumor cell aggressiveness. Initially, we will perform co-culture experiments using Boyden-chambers or cell culture supernatants, in which cells with high expression levels of HIF2α or with SDHB impairment are co-cultured with their respective controls (non-HIF2α- or non-SDHB-driven cells) to assess whether secreted factors contribute to the disease phenotype. We will investigate effects on proliferative (viability, cell growth, and apoptosis assays) and pro-metastatic (motility, migration, invasion, and adhesion assays) properties of the cells.

To determine which factors are most important, Prof. Manuel Mayr (KCL) will carry out secretome (proteomics) analyses, and identified factors will be validated (western blot analysis or ELISAs). To demonstrate conclusively that the secretory factors are responsible for the observed effects, two of the identified factors will be added individually to the cell culture medium of the control cells and proliferative and pro-metastatic endpoints will be measured. Our long-term strategy involves to verify our in vitro results by targeted studies on available PPGL tumor specimens (immunohistochemistry, proteomics). Better understanding of intra-tumor heterogeneity, its influence on different subpopulations and role in the development of metastasis will aid in identifying new therapeutic approaches for metastatic PPGLs.

Partially funded.

Non-invasive brain stimulation is a powerful treatment for an increasing number of psychiatric disorders including schizophrenia (SZ). Converging lines of evidence from human and animal model studies using structural magnetic resonance imaging (MRI) suggest that the beneficial clinical and behavioural effects of non-invasive brain stimulation (NIBS) are accompanied by neuroanatomical remodelling. Whether these brain structural changes mediate these effects is however unclear. Given the emerging interest in the use of NIBS to treat neuropsychiatric disorders, such as schizophrenia, it is critical to address this gap in our knowledge. The Bernhardt lab (TU Dresden) recently contributed to the finding that non-invasive stimulation of the prefrontal cortex alleviated behavioural deficits in a rat model of relevance for SZ based on maternal immune activation (MIA), for which archival structural MRI data is also available.

Objective
The objective of this project is to determine if the effects of NIBS on behaviour in the rat MIA model are accompanied or mediated by neuroanatomical remodelling, as measured by structural MRI. This will be achieved in collaboration with the Vernon Lab (KCL) who has a proven track record of expertise in data-driven computational analysis of rat structural MRI data and mapping brain-behaviour relationships using multivariate statistics.

Completely funded

Insulin hypersecretion, consecutive hyperinsulinemia and !-cell dysfunction occurs in females exposed to an excess of androgens either during foetal development or in adulthood, e.g. in adult females with PCOS. Furthermore, exposure to oestrogenic endocrine disrupters act through extranuclear pathways to compromise pancreatic development and function. A plasma membrane, androgen receptor has been
discovered to exist in addition to the canonical androgen signalling pathway involving the nuclear androgen receptor. This membrane androgen receptor is abundantly expressed in the pancreatic ß-cells and remarkably appears to be an androgen-gated zinc importer, SLC39A9 which acts via activation of Gproteins. It belongs to a family of zinc importers with 14 members in human. Surprisingly, there is no structure of eukaryotic SLC39 proteins. Moreover, so far there are successful purification protocols that would allow to reconstitute the receptor in membrane mimetic systems that would allow functional characterisation of that protein.

Recently, the Coskun group have succeeded in expressing and puryfing the SLC39A9 from E. coli and SF9 cells and we now wish to proceed with large scale protein production that
will allow us to reconstitute the protein in lipid enviroments of our choice and to perform structural studies using cryo-EM. We therefore request for funding for three months for a KCL student (Ms Rui Wang) supervised by Prof Christer Hogstrand to produce SLC39A9 in the laboratory of Prof. Dr. Ünal Coskun. Ms Wang is in the first year of her PhD project on SLC39A9 and collaboration with Prof Dr Coskun would be an excellent complement to her studies.

Partially funded.

Project group: Prof. Bärbel Fürstenau, Prof. Dr. Juliet Foster, Dr. Patricia A. Zunszain, Ianina Scheuch, Dr. Gisele Dias

The proposed project will extend an international interdisciplinary collaboration between Technische Universität Dresden (TU Dresden) and King’s College London (KCL) with the focus on students’ wellbeing and resilience competency development. The strategic aims of the project are 1) to transfer research-based knowledge and expertise on wellbeing and resilience competency development to current and future professionals, to implement the competency program in TU Dresden’s university portfolio, evaluating it and jointly publishing the result; 2) to extend internal and external international interdisciplinary networking activities and to establish infrastructure for future cooperation. The project, thus, provides opportunities for exchange of early career researchers and students. Furthermore, it bridges research in the fields of business education, psychology and neuroscience, to strengthen an interdisciplinary research network, and to build the grounds for future research and funding.

Partially funded.

Project group: Prof. Heinz Reichmann, Prof. K Ray Chaudhuri, Dr. med. Lisa Klingelhöfer, Dr. Valentina Leta

Background: Helicobacter pylori (HP) is a gram-negative bacterium frequently infecting the human gastrointestinal tract with a prevalence ranging from 24% to 79% globally. Although often asymptomatic, the infection can be associated with nausea, vomiting, abdominal bloating and pain and potentially lead to gastritis, peptic ulcers and even gastric cancer. Diagnosis can be easily made by using non-invasive tests such as urea breath or stool antigen tests, and treatment consists of antibiotics combined with acid-suppressing drugs.
Recent metanalyses suggested a potential role for the infection in the pathogenesis of Parkinson’s disease (PD); moreover, HP infection may also represent an obstacle to levodopa absorption via a variety of putative mechanisms, including alteration of gastric pH, induction of delayed gastric emptying, and damage of the mucosa (site of drug absorption), potentially leading to fluctuating response to levodopa and worse health related quality of life (HrQoL).

Objective: To investigate whether HP infection in PD can lead to clinically relevant altered motor and non-motor status, response to levodopa, gastrointestinal dysmotility and worse HrQoL. This project will associate TUD and KCL and will be part of an already established international collaboration between KCL and the Parkinson Research Alliance of India (PRAI) investigating the clinical impact of HP infection in a multicentre cohort of patients with PD. In addition, this study will include the use of the Parkinson`s KinetiGraph (PKG) as an objective remote measure for motor and partly non-motor status. Further the Gut Dysmotility Questionnaire (GDQ) will be used, developed in the context of a previous collaboration between KCL and TUD supported by the transCampus initiative in 2020.

Partially funded.

Mutation of p53 (mutp53) is a hallmark of tumor development and found in ~50% of all tumors, leading to loss-of-function or gain-of-function of this important tumor suppressor. Consequently, cancer cells resist p53-dependent cell cycle checkpoints and intrinsic cell death. This is particularly true for about 70-80% of head and neck squamous cell carcinoma (HNSCC) that only poorly respond to the combination of radiotherapy (RT) and chemotherapy (CT). Recently, human papillomavirus (HPV) has emerged as an additional risk factor for the development of cancers of the oropharynx. Patients with HPV-associated HNSCC have an improved overall and disease-specific survival. HPV-derived HNSCC express wildtype p53 (wtp53) but HPV-E6 oncoprotein stimulates ubiquitination and proteasomal degradation of p53. Residual wtp53 is activated when exposed to DNA damage and is believed as one of the causes for better treatment responses.
Although only 20% of malignant melanoma (MM) carry p53 mutations, MM is known to be chemoresistant and responsible for 90% of deaths caused by skin cancer. Hence, MM cells must be able to adapt mechanisms suppressing wtp53 functions. We have recently identified a non-canonical role of caspase-8 in the nucleus that allows tumor cells with wtp53 to establish a de facto p53 protein loss, shifting cell fate from cell cycle arrest and apoptosis towards mitotic cell division at the G2/M checkpoint. Nuclear caspase-8-dependent cleavage of deubiquitinase USP28 protein was found to be responsible for destabilization of wtp53 leading to resistance to DNA damage and consequently tumor relapse (https://pubmed.ncbi.nlm.nih.gov/31982308).
This joint TransCampus study aims to dissect the interplay of caspase-8 and p53 in chemoresistance of two severe cancer types that express either mutp53 (HNSCC), harbor HPV-driven suppression of wtp53 (HPV-HNSCC) or express functional wtp53 (MM).
Hence, we will:

• Study the changes in expression and localization of caspase-8 and p53 after treament with chemotherapy, radiotherapy and targeted drugs.
• Genetically modify 3 HNSCC, 3 HPV-HNSCC, 6 MM (3 BRAF- and 3 NRAS-mutated) cell lines to stably express "no" p53, wtp53, mutp53 (R248W and R175H), respectively, and investigate chemo-responsiveness by PI staining (IncuCyte).
• Correlate the specific p53 expression status with the expression level and the subcellular localization of caspase-8 (ICC).
• Performing retrospective patient studies (IHC, RNAseq) we will correlate the subcellular caspase-8 localization with the individual therapeutic outcome (death/survival) in mutp53 expressing HNSCC, HPV-driven wtp53 suppressing HPV-HNSCC and functional wtp53 expressing MM.

The combination of our molecular and translational approach will help to better understand the impact of the interplay of caspase-8 and p53 in therapy responsiveness and may pave the way for the identification of new therapeutic approaches to provide improved and even tailored treatment options.

Partially funded.

Specific brain regions such as the hippocampus possess adult neural stem cells (ANSCs) which give rise to new neurons throughout life and provide structural and functional brain plasticity. This process is so-called adult hippocampal neurogenesis (AHN) and its importance has been implicated in mood regulation as well as cognition. Unfortunately, AHN altered by stress, aging, and in neurodegenerative diseases such as Alzheimer’s disease (AD). Especially, stress, aging, and neurodegenerative diseases cause similar psychiatric symptoms such as anxiety and depression. Thus, the identification of convergent/common targets from those challenges iscritical for developing diagnostic and therapeutic means.

The Thuret lab has been studying the relationship between mood dysregulation and adult
hippocampal neurogenesis. For instance, the team identified stress-induced  reorganization ofgenetic programs in the mouse model, which may underlie changes in AHN. In parallel, the Toda lab has sought age-related epigenetic regulators of AHN, and recently identified lamin B1, one of the nuclear lamins and an essential component of the nuclear lamina, as a cell intrinsic epigenetic regulator of aging of adult neural stem cells (ANSCs) and age-related anxiety.  We hypothesize that lamin B1 is a convergent target of aging and stress in the dysregulation of AHN, (Fig. 2B). In this project, we aim to identify upstream regulators of lamin B1 by combining complementary expertise in stem cell aging (Toda lab) and stress signaling (Thuret lab) in order to decipher mechanistic links from stress/aging to mood dysregulation.

Partially funded.

There is an increasing interest in entrepreneurs' resilience and well-being from researchers and practitioners alike. This is because entrepreneurs’ resilience and ‘happiness’ relate to their creativity, productivity, and their business' success (e.g., Stephan, 2018; Wach, Stephan, Weinberger, & Wegge, 2020; Weinberger, Wach, Stephan, & Wegge, 2018). The Covid-19 pandemic has accelerated this interest. For instance, our own international project “Supporting Entrepreneurship during the Covid-19 Pandemic: A Global Study of Entrepreneurs' Resilience and Well-being” documented the profound threat to entrepreneurs' well-being and their businesses stemming from the Covid-19 pandemic. While entrepreneurs were occasionally thriving, most struggled with increased stress and impaired mental well-being. Many lacked strategies to protect their well-being and some gave up eventually their businesses because of it. Our successfully accomplished transCampus project entitled “Resilience and well-being of entrepreneurs through the COVID-19 pandemic” suggests that the well-being of German entrepreneurs surveyed during the pandemic was 11% lower compared to pre-pandemic. We also find nearly half (46%) of the entrepreneurs in our study who either agreed or strongly agreed that they experienced distorted sleep. Moreover, our surveyed entrepreneurs reported restricted ability to disconnect mentally from work during their leisure time. Overall, we found both physiological and mental recovery, as well as well-being, to be significantly lower in women than men entrepreneurs.

The proposed project departs from insights such as these outlined above and designs and delivers an intervention to equip entrepreneurs with so-called recovery strategies, i.e. strategies that are proven to aid recovery from work stress and thereby allow entrepreneurs to safeguard their well-being. Ingraining these recovery strategies into entrepreneurs’ daily routines will lay foundation for their long-term resilience to stress. Existing research into recovery documents its positive effects but also highlights how difficult it can be to engage in recovery when work is particularly stressful (Sonnentag, 2018). This led the applicants to call for and initiate a dedicated research agenda on entrepreneurs' recovery (Wach et al., 2020, Weinberger et al., 2018; Williamson, Gish, & Stephan, 2021). The proposed project entitled “Raising entrepreneurs' resilience through recovery: A daily intervention study” is a critical step to develop this research agenda by moving from documenting challenges in entrepreneurs’ well-being to implementing and testing recovery strategies to help enhance entrepreneurs' well-being and their resilience. This lays the foundations for a development of a joint application for third-party funding to be submitted to the DFG as an individual research grant entitled “Creating a recovery mindset in entrepreneurs: Effects on resilience, well-being, and performance”.

Completely funded.