ERC FUNDED PROJECTS

The aetiology of many musculoskeletal (MS) diseases is related to biomechanical factors. However, the tools to assess the biomechanical condition of patients used by clinicians and researchers are often crude and subjective leading to non-optimal patient analyses and care. In this project innovations related to imaging, sensor technology and biomechanical modelling are utilized to generate versatile, accurate and objective methods to quantify the (pathological) MS condition of the lower extremity of patients in a unique manner. The project will produce advanced diagnostic, pre-planning and outcome tools which allow clinicians and researchers for detailed biomechanical analysis about abnormal tissue deformations, pathological loading of the joints, abnormal stresses in the hard and soft tissues, and aberrant joint kinematics. The key objectives of this proposal are: 1) Develop and validate image-based 3-D volumetric elastographic diagnostic methods that can quantify normal and pathological conditions under dynamic loading and which can be linked to biomechanical modelling tools. 2) Create an ultrasound (US)-based system to assess internal joint kinematics which can be used as a diagnostic tool for clinicians and researchers and is a validation tool for biomechanical modelling. 3) Generate and validate an ambulant functional (force and kinematic) diagnostic system which is easy to use and which can be used to provide input data for biomechanical models. 4) Create and validate a new modelling approach that integrates muscle-models with finite element models at a highly personalized level. 5) Generate biomechanical models which have personalized mechanical properties of the hard and soft tissues. 6) Demonstrate the applicability of the personalized diagnostic and pre-planning platform by application to healthy individuals and patient subjects. Support from the ERC will open new research fields related to biomechanical patient assessment and modeling of MS pathologies.

2 456 400 €

Start date: 2013-05-01, End date: 2018-04-30

Celiac disease affects at least 1% of the world population. Its onset is triggered by gluten, a common dietary protein, however, its etiology is poorly understood. More than 80% of patients are not properly diagnosed and they therefore do not follow a gluten-free diet, thereby increasing their risk for disease-associated complications and early death. A better understanding of the disease biology would improve the diagnosis, prevention, and treatment of celiac disease. This project investigates the disease mechanisms in celiac disease by using predisposing genes and genetic variants as disease initiating factors. Specifically, it will investigate if long, intergenic non-coding RNAs (lincRNAs) are causally involved in celiac disease pathogenesis by regulating protein-coding genes and pathways associated with the disease. This project is based on two important observations by my group: (1) Our genetic studies, which led to identifying 39 celiac disease risk loci, suggest that the mechanism underlying the disease is largely governed by dysregulation of gene expression. (2) We uncovered a previously unrecognized role for lincRNAs that provides clues as to exactly how genetic variation causes disease, as this class of biologically important RNA molecules regulate gene expression. The research will be performed in CD4+ T cells, a severely affected cell type in disease pathology. I will first use celiac disease-associated protein-coding genes to delineate their regulatory pathways and then study the transcriptional programs of lincRNAs present in celiac disease loci. Next I will combine the information and investigate if the expressed lincRNAs modulate the pathways and affect T cell function, thereby discovering if lincRNAs are a missing link between non-coding genetic variation and protein-coding genes. Our findings may well lead to potential therapeutic targets and provide a solid scientific basis for new diagnostic markers, particularly biomarkers, based on genetics.

2 319 914 €

Start date: 2013-02-01, End date: 2018-11-30

"Functional activity of proteins is tightly controlled via reversible post-translational modifications including phosphorylation, acetylation and ubiquitylation. These modifications enable the orchestration of cellular responses to a wide variety of stimuli. Due to these modifications, proteomes are overwhelmingly complex. Progress in the field has been greatly accelerated by the development of novel approaches to study these post-translational modifications at a proteome-wide scale using the sensitivity and robustness of mass spectrometry (MS). This has enabled the identification of thousands of dynamically regulated phosphorylation, acetylation and ubiquitylation sites by MS. The functional significance of these modifications is now being addressed worldwide at an unprecedented scale. In contrast, global understanding of ubiquitin-like signalling networks in a site-specific manner is very challenging. Over the last few years, my lab has established novel methodology for the purification and identification of endogenous SUMO target proteins and SUMOylation sites of endogenous targets. The first aim of this project is to uncover small ubiquitin-like modifier (SUMO) signalling pathways in a site-specific manner at a proteome-wide level. The second aim of this project is to reveal how SUMOylation cooperates with ubiquitylation to maintain genome integrity. SUMOylation plays a critical role during the DNA damage response, an important barrier against genome instability linked diseases including cancer and neurodegeneration. Selected target proteins will be studied at the functional and mechanistic level to obtain novel insight in cellular processes that protect against genome instability. The developed methodology is generic and can be applied to study all ubiquitin-like proteins at a proteome-wide level in a site-specific manner, enabling global understanding of ubiquitin-like signalling networks in health and disease."

1 517 699 €

Start date: 2013-01-01, End date: 2017-12-31

The vast quantity of information in our genomes must continuously be read out and processed. This is done by proteins, acting either individually or as part of larger protein complexes. How this genome processing operates successfully, given the crowded nature of the DNA track as well as its mechanical constraints and coiling, is a question of fundamental interest. We will investigate the dynamics of genome processing during DNA transcription and replication. Throughout, we ask the question, what brings these processes to a halt? Focusing on both individual molecular motors and protein complexes, we ask, when do these stall? Both mechanical constraints such as the accumulation of torsional stress and the presence of proteins along the DNA helix may conspire, intentionally or not, to halt transcription and replication. Specifically, we will investigate how RNA polymerases, replicative helicases, and replisomes can be derailed or stalled. These experiments will shed light on the mechanochemical cycle of RNA polymerase, on its motion along a complex track, on the physical interactions that occur between helicases and proteins at termination, and on replisome dynamics near stall. They will also quantify the effects of torsional stress in DNA on the advancement of transcription and replication. The proteins and protein complexes studied here include principal actors in processes essential to cell survival. Understanding the manners in which they can fail will illuminate their mechanism and cellular roles. The powerful single-molecule instrumentation that we have developed in recent years allows one to visualize individual proteins while precisely controlling and monitoring the state of DNA. When harnessed to answer these profound biological questions, we extend not only our knowledge of biological processes but also our understanding of how simple physical principles can govern a wide range of phenomena, thereby having an impact on biology and physics alike.

1 500 000 €

Start date: 2013-01-01, End date: 2017-12-31