320 Projects, page 1 of 64
- Project . 2018 - 2019Open Access mandate for Publications and Research dataFunder: EC Project Code: 743290Overall Budget: 187,420 EURFunder Contribution: 187,420 EURPartners: UB
Despite the existence of various novel anti-cancer treatments, drug resistance remains a major cause of death in patients with disseminated cancer. To increase specificity and efficacy, modern treatment strategies in molecular oncology employ the “synthetic lethality” concept. An example are BRCA1/2-deficient breast and ovarian cancers that lack DNA repair by homologous recombination (HR). Due to this defect, tumor cells rely more on other DNA repair pathways. When such alternative pathways are jammed, e.g. by poly(ADP-ribose) polymerase inhibitors (PARPi), normal cells with intact HR can survive, whereas cancer cells die. However, even with this sophisticated treatment strategy, resistance to PARPi still occurs and greatly reduces patient survival. The mechanisms driving this resistance are still largely unknown. The main goal of this project is to advance the knowledge on therapy resistance by using a genetically engineered mouse model of BRCA2-deficient breast cancer, which closely mimics the human disease. Like in patients, cancer cells in these animals eventually escape from therapy. I will start by synergizing the next generation sequencing analysis of spontaneous resistant mouse tumors with functional genetic screens using the CRISPR/Cas9 technology. This combination has yielded interesting candidate genes whose loss of function may cause resistance. Two promising candidates, MDC1 and Claspin, will be further investigated using innovative and physiologically relevant 3D tumor organoid cultures. Moreover, I will apply my expertise in modern imaging technology to develop novel approaches to visualize DNA repair dynamics in resistant tumors in vitro and in vivo. I am convinced that by understanding basic resistance mechanisms, smart biosensors can be built to image the DNA damage response and eventually improve clinical decision making. I believe this project will have an impact on the design of strategies to overcome therapy escape in human cancer patients.
- Project . 2019 - 2021Open Access mandate for Publications and Research dataFunder: EC Project Code: 842868Overall Budget: 191,149 EURFunder Contribution: 191,149 EURPartners: UB
PROSPER is an interdisciplinary project that seeks to understand the politics of rule-making in the global trade regime. It primarily aims to examine how the growth of internationalization of production networks enables private actors – i.e. multinational companies (MNCs) – to be active in the shaping of international economic policies, such as trade agreements and regulatory standards. PROSPER will primarily investigate the extent to which MNCs are able to orchestrate political mobilization of their subsidiaries for coordinated lobbying and impose rules and standards upon firms along their supply chains. Applying international political economy (IPE) insights from the fields of political science, economics, and international law, the projects proposes that firms’ globalization strategies and their degree of integration into global production networks significantly affect their ability to be active in shaping global rules and standards. In order to test the empirical implications of the proposed theory, PROSPER will employ a mixed-method research design using quantitative analysis and in-depth case studies. The project will construct a comprehensive new dataset of MNCs and triangulate the results achieved through statistical analysis via comparative cases studies. As a result, by combining insights from political science, economics, and international law, the project will help us understand the dynamics of economic globalization and the role of private actors in the global trade governance.
- Project . 2018 - 2020Open Access mandate for PublicationsFunder: EC Project Code: 744257Overall Budget: 187,420 EURFunder Contribution: 187,420 EURPartners: UB
Recently, it has emerged that early life exposure to commensal microbes is crucial to instruct our immune system and prevent later life autoimmune and metabolic diseases. The host lab now showed that this education begins even earlier – during gestation by signals from the maternal intestinal microbiota. Using the E. coli strain HA 107, genetically engineered to grow in vitro without the ability to persist in vivo, they demonstrated that transient intestinal colonisation of pregnant germ-free mouse dams drives neonatal innate immune maturation. However, the long-term consequences of maternal microbiota cues especially for the adaptive immune system of the adult offspring remain elusive. The MEMORIS project (Maternal Enteric Microbiota for Offspring's Repertoire development & Illness Susceptibility) shall elucidate the long-term consequences of maternal microbial signals for the offspring’s adaptive immune system and disease susceptibility. My specific aims are to reveal the consequences of gestational colonisation for the offspring’s (1) own intestinal microbiota composition and metabolism; (2) adaptive immune repertoire development; and (3) susceptibility to autoimmune and metabolic diseases. For this, I will colonise offspring of gestationally colonised versus germ-free mouse dams at birth and by (1) metagenomic, metatranscriptomic and metabolomic read-outs assess its dynamic microbiota development. (2) Flow cytometric and transcriptional profiling, immunglobulin gene sequencing and bacterial FACS will reveal adaptive immune repertoire maturation. Based on these results I will (3) elucidate the role of maternal microbiota signals for disease susceptibility using NOD mice modeling type 1 diabetes and high fat diet-induced non-alcoholic fatty liver disease. I would like to establish the concept that our susceptibility to autoimmune and metabolic diseases is influenced during a “window of opportunity” that opens – not just at birth – but already during pregnancy.
- Project . 2022 - 2024Open Access mandate for Publications and Research dataFunder: EC Project Code: 101027428Overall Budget: 203,149 EURFunder Contribution: 203,149 EURPartners: UB
Nicotinic acetylcholine receptors (nAChRs) are transmembrane ligand gated ion channels composed of five subunits and encoded by 16 genes. Depending on the subunit composition nAChRs have different properties and functions. It is widely accepted that smoking tobacco is correlated with several types of cancers and that nicotine and tobacco-derived nitrosamines are known to activate nAChRs contributing to oncogenic processes. To date the question of whether nAChRs contribute to the cellular malfunctions involved in prostate and colon cancer still remains unanswered. Our preliminary results show for the first-time different expression levels of nAChRs subunits in prostate and colon cancer cell lines. Most strikingly is the clear difference of expression of nAChRs subunits between cancerous vs. non-cancerous cells, depending on the aggressiveness and cell type. The question arises whether these differences have a physiological impact. In the present project I will investigate the pathophysiological role of nAChRs in prostate and colorectal cancer. My aim is to (1) Identify and characterize nAChRs involved in prostate and colon cancer; (2) study the role of nAChRs in migration, proliferation and invasion in prostate and colon cancer; (3) the influence of a duplicated isoform of the α7 nAChR subunit, dupα7, and its anti-angiogenic properties in CRC and PCa; and (4) the role of chemotherapeutic drugs, which could augment nAChRs expression in cancer and contribute to chemoresistance. The present project will be performed at the laboratory of Dr. Peinelt University of Bern, an established research group with a focus on the pathophysiology of ion channels in prostate and colorectal cancer and in collaboration with the Urology Department of the University Hospital Inselspital Bern. The Marie Curie IF will help me to further develop leadership skills, scientific maturity and independence and will be crucial for my aim to obtain an independent academic position in the future.
- Project . 2020 - 2023Open Access mandate for Publications and Research dataFunder: EC Project Code: 896310Overall Budget: 304,724 EURFunder Contribution: 304,724 EURPartners: UB
Despite significant progress in drug therapies for breast cancer, about one fourth of patients still do not survive the disease. Modern, targeted therapies have been proposed to cure the more advanced and aggressive cases of breast cancer. However, non-genetic and genetic mechanisms of drug resistance currently limit the promise of targeted therapy. NOSCAR aims to define the oncogenic Ras/Erk and PI3K/Akt signalling states relevant to breast cancer oncogenic mutations, and delineate the mechanisms which enable development of cancer resistance to targeted therapies. NOSCAR’s objectives are: Using a quantitative cell biology framework that combines a multiplexed biosensor system that reports on Erk/Akt dynamics at single cell level, computer vision, and statistical modelling, I will: (1) produce an atlas of single-cell Erk/Akt dynamic signalling patterns that are associated with a compendium of clinically-relevant breast cancer mutations; (2) measure the signalling states in cells perturbed with clinically-relevant drugs that target different components of the Ras/Erk and PI3K/Akt pathways to evaluate how the oncogenic signalling network is rewired by drug treatment; (3) measure signalling dynamics in 3D spheroid cultures and patient-derived organoids to explore how a self-organizing cellular ecosystem can spatially control signalling at the single cell level to locally control fate decisions, and how the latter process is compromised by an oncogenic mutation. This will provide new insights about tumor heterogeneity and signaling network structures that confer robustness against drug perturbations. We expect to identify vulnerabilities that might be efficiently targeted by drug combinations, providing new avenues to treat breast cancer. The planned research together with training and mentoring that I will receive thanks to the fellowship, will enable to successfully restart my career in research and will significantly benefit my further academic career prospects.