ERC FUNDED PROJECTS

"Regulation and fidelity of gene expression is fundamental to the differentiation and maintenance of all living organisms. While historically attention has been focused on the process of transcriptional activation, we predict that RNA turnover pathways are equally important for gene expression regulation. This has been implied for selected protein-coding RNAs (mRNAs) but is virtually unexplored for non-protein-coding RNAs (ncRNAs). The intention of the EURECA proposal is to establish cutting-edge research to characterize mammalian nuclear RNA turnover; its factor utility, substrate specificity and regulatory capacity. We foresee that RNA turnover is at the core of gene expression regulation - forming intricate connection to RNA productive systems – thus, being centrally placed to determine RNA fate. EURECA seeks to dramatically improve our understanding of cellular decision processes impacting RNA levels and to establish models for how regulated RNA turnover helps control key biological processes. The realization that the number of ncRNA producing genes was previously grossly underestimated foretells that ncRNA regulation will impact on most aspects of cell biology. Consistently, aberrant ncRNA levels correlate with human disease phenotypes and RNA turnover complexes are linked to disease biology. Still, solid models for how ncRNA turnover regulate biological processes in higher eukaryotes are not available. Moreover, which ncRNAs retain function and which are merely transcriptional by-products remain a major challenge to sort out. The circumstances and kinetics of ncRNA turnover are therefore important to delineate as these will ultimately relate to the likelihood of molecular function. A fundamental challenge here is to also discern which protein complements of non-coding ribonucleoprotein particles (ncRNPs) are (in)compatible with function. Balancing single transcript/factor analysis with high-throughput methodology, EURECA will address these questions."

2 497 960 €

Start date: 2014-04-01, End date: 2019-03-31

The goals are: 1) to develop a universal laboratory-based 4D X-ray microscope with potentials in the broad field of materials science and beyond; 2) to advance metal research by quantifying local microstructural variations using the new 4D tool and by including the effects hereof in the understanding and modelling of industrially relevant metals. Today, high resolution 4D (x,y,z,time) crystallographic characterization of materials is possible only at large international facilities. This is a serious limitation preventing the common use. The new technique will allow such 4D characterization to be carried out at home laboratories, thereby wide spreading this powerful tool. Whereas current metal research mainly focuses on average properties, local microstructural variations are present in all metals on several length scales, and are often of critical importance for the properties and performance of the metal. In this project, the new technique will be the cornerstone in studies of such variations in three types of metallic materials: 3D printed, multilayered and micrometre-scale metals. Effects of local variations on the subsequent microstructural evolution will be followed during deformation and annealing, i.e. during processes typical for manufacturing, and occurring during in-service operation. Current models largely ignore the presence of local microstructural variations and lack predictive power. Based on the new experimental data, three models operating on different length scales will be improved and combined, namely crystal plasticity finite element, phase field and molecular dynamics models. The main novelty here relates to the full 4D validation of the models, which has not been possible hitherto because of lack of sufficient experimental data. The resulting fundamental understanding of the inherent microstructural variations and the new models are foreseen to be an integral part of the future design of metallic materials for high performance applications.

2 496 519 €

Start date: 2018-10-01, End date: 2023-09-30

The ribotoxic stress response (RSR) surveys the structural and functional integrity of ribosomes and is triggered by diverse groups of ribotoxins (e.g. ricin), UV irradiation and some chemotherapeutics. When presented with impaired ribosomes, the proximal MAPKKK ZAK activates MAP kinases p38 and JNK to initiate a powerful inflammatory response. This signalling contributes to the detrimental reactions to ribotoxins and fatal side effects of cancer therapy. However, despite decades of research into the RSR, the physiological relevance of the underlying pathway in whole organisms is unknown. I hypothesize that the RSR constitutes a general translation quality control pathway and hence I aim to uncover the physiological and pathological implications of RSR impairment in mice and nematodes. In one line of investigation, I will elucidate the connections between UV radiation and RSR-mediated p38 activation. I hypothesize that this signalling pathway is critical for sunlight-induced skin inflammation and development of skin cancers of different cellular origins. Rewardingly, we found that cells from our ZAK knockout (KO) mice are refractory to UV-induced p38 activation, which is a significant contributor to skin cancer development. My team has also observed deregulation of protein translation in RSR-deficient human and mouse cells, and a reduced lifespan of ZAK KO nematodes. Thus encouraged, I will determine the impact of the RSR pathway on cancer development and aging processes in mice, and I will unravel the molecular connections between defective ribosomes, RSR activation and regulation of translation. Finally, I am in a unique position to evaluate the RSR as a putative drug target and I will investigate the potential of ZAK inhibition to treat or prevent skin cancer, and to remedy inflammation arising from infection with ribotoxin-producing bacteria. In sum, PHYRIST will yield the first detailed insight into the in vivo relevance of the ribotoxic stress response.

1 997 678 €

Start date: 2020-06-01, End date: 2025-05-31

There is currently no medical cure for the millions of individuals affected by inflammatory bowel disease (IBD). These patients suffer from bleeding along the gastrointestinal tract due to epithelial ulceration, which causes severe abdominal pain, diarrhoea and malnutrition. This is due to the severely compromised integrity of the intestinal epithelium. I propose that patients with IBD will benefit from an intestinal epithelial transplant. The objectives of this research programme are two fold. Firstly, I propose to perform preclinical testing of human intestinal epithelium to pave the way for their inclusion in clinical trials for IBD patients. This will be based on a combination of state-of-the-art cell culture methods with novel transplantation methodology. By combining analysis of intestinal epithelial cells from various developmental stages, I will be able to identify the most suitable source for transplantation and define how adult stem cells are specified in the tissue. Secondly, I will utilise an in vitro culture system to identify the transcriptional networks responsible for the maturation of the foetal intestinal epithelium. Tissue maturation currently constitutes a major roadblock in regenerative medicine as cells derived from foetal and pluripotent stem cells have foetal properties. Understanding this process will therefore improve our ability to generate sustainable sources of cells for transplantation, which is pivotal for future therapies relying on regenerative medicine and in vitro modelling of disease The proposed research programme will have significant clinical and biological impact. Clinically, it provides the framework for initiating clinical trials for patients with IBD and protocols to obtain mature adult epithelium for in vitro disease modelling. From a biological perspective, we will gain insights into how specific signalling networks maintain specific cell states and dictate tissue maturation.

2 000 000 €

Start date: 2016-08-01, End date: 2022-07-31