Grants and Support

ERC Grants

ERC grantees at LUMC

The European Research Council (ERC) provides attractive, long-term funding to support excellent investigators to pursue ground-breaking, high-gain/ high-risk research. Research funded by the ERC is expected to lead to advances at the frontiers of knowledge and to set a clear and inspirational target for frontier research across Europe. The ERC was launched in 2007 and is currently part of Horizon2020, the EU programme for Research and Innovation.

LUMC is delighted to be/have been Host Institution of 20 ERC projects in total (5 Advanced grants, 4 Consolidator grants, 9 Starting grants and 2 Proof of Concept grants). Please note that two ERC Starting Grants have been transferred to LUMC during the project and one ongoing ERC Starting Grant has been transferred from LUMC to another Host Institution (marked with * below). In addition, the eligibility window of the ERC Starting Grants until 2012 was up to 12 years post-PhD (the ERC Consolidator Grant scheme was launched in 2013).

The ERC-granted Principal Investigators are listed below, including more information about their projects.

ERC Advanced Grant - 2015 Jacques van Dongen: Title: Recirculated tissue macrophages (TiMa) in blood: Novel approach to early diagnosis and treatment monitoring in oncology
Acronym: TiMaScan

Prof. Jacques J.M. van Dongen, MD, PhD (link)
Department of Immunohematology and Blood Transfusion

ERC Advanced Grant 2015 - panel LS7
EC contribution: EUR 2.500.000
Start date: 2016-11-01 - End date: 2021-10-31
Host institution: LUMC

Abstract:
In the ageing European population, cancer has become the most common cause of death. Consequently, screening programs aim at early detection of cancer, while scanning/imaging technologies, serum assays and regular biopsies aim at monitoring of treatment effectiveness to improve cure rates and increase quality-of-life, thereby also attempting to reduce health care costs. However, in many cases the screening and monitoring methods do not provide sufficient sensitivity and specificity. Consequently novel diagnostic techniques are required.
Completely Novel Concept: Sensitive intra-tissue total body scanning is continuously performed by our immune cells, particularly by monocytes and macrophages. Tissue macrophages (TiMas) continuously phagocytize and digest apoptotic cells and tissue debris. In cancer, many more TiMas are present to keep the involved tissue debris-free. When TiMas have fulfilled their local tissue-cleaning task, they can migrate via lymph vessels to lymph nodes and potentially recirculate to the blood stream, where they can be detected by flow cytometry and evaluated for the contents of their phagolysosomes. With State-of-the-Art technologies, this high-risk project aims to unravel phagocytosis of cancer cells, their digestion into tissue-specific and/or cancer-associated protein fragments, the migration/recirculation of TiMas to blood, and the detection of intra-phagosomal protein fragments in blood TiMas by antibodies. Building on this information, flowcytometric scanning of blood TiMas (TiMaScan) will be developed into a novel tool for early diagnosis and monitoring of treatment in oncology, focusing on colon, lung, breast and prostate cancer. TiMaScan diagnostics will be minimally-invasive (~1ml of blood), rapid, accurate, broadly available and cost-effective, only requiring a flowcytometer. The TiMaScan Concept might also be applicable for early diagnosis and disease monitoring in other medical fields, such as neurodegenerative and infectious diseases.

LUMC press release about this ERC grant
ERC Advanced Grant - 2015 Sjaak Neefjes: Title: The ER located master regulation of endosomal positioning and further movements
Acronym: ERCOPE

Prof. Sjaak Neefjes, PhD (link)
Department of Chemical Immunology

ERC Advanced Grant 2015 - panel LS3
EC contribution: EUR 2.383.625
Start date: 2016-09-01 - End date: 2021-08-31
Host institution: LUMC

Abstract:
The endo-lysosomal system is critical to diverse processes, including protein homeostasis, signaling and antigen presentation. The vesicular compartment is organized as a collective unit wherein the bulk of endosomes derived from disparate origins resides in a cloud in the perinuclear region and extends outwards to include quickly moving vesicles in the periphery. At this busy intersection between the endocytic and biosynthetic pathways, lies the late endosomal compartment, responsible for protein degradation and antigen processing. In dendritic and other immune cells, this major constituent of the perinuclear cloud serves as a hub for MHC class II antigen loading. Previous work by us and others has elucidated key elements of MHC class II biology through the study of late endosomal transport to and from the cell periphery. It is clear that cell biology of endosomes is modulated by their proximity to other membrane compartments during transport, maturation, cargo selection and delivery and even during cytokinesis in cell division. However, how endosomal positioning in the perinuclear cloud and how their release for further transport is controlled remains largely unknown. The aim of this proposal is to define the molecular basis for endosomal positioning and then to interrogate the relationship between spatial regulation of the endocytic compartment and its functions with respect to i) MHC class II antigen presentation, ii) bacterial infection and iii) mitotic resolution. From a genome-wide siRNA screen for factors influencing MHC class II biology, we have identified a unique and previously uncharacterized ubiquitin ligase that resides in the ER membrane, from where it controls endosomal positioning and times their arrivals and departures as a function of its catalytic activity. On this basis, the work proposed herein is poised to resolve an entirely new molecular network in control of endosomal biology with implications for diverse biological processes.

Sjaak Neefjes already received an ERC Advanced Grant 2009, with the Netherlands Cancer Institute as host institution.
ERC Advanced Grant - 2014 Andrew Webb: Title: Novel materials to improve magnetic resonance imaging
Acronym: NOMA-MRI

Prof. Andrew Webb, PhD (link)
Department of Radiology

ERC Advanced Grant 2014 - panel LS7
EC contribution: EUR 2.263.692
Start date: 2015-11-01 - End date: 2020-10-31
Host institution: LUMC

Abstract:
MRI is one of the most important human clinical imaging modalities. Over the past decade many technological advances have improved image quality substantially. One of the critical trends has been the move towards higher magnetic fields, which has transformed many clinical applications, but has also introduced significant challenges. These higher fields correspond to higher operating frequencies, which lead to increased image non-uniformities, impairing clinical interpretation, and higher power deposition in the patient, posing significant safety issues. In addition, as the population as-a-whole becomes more obese, high quality MR images become increasingly difficult to acquire even on clinical 3 Tesla scanners. In order to tackle these challenges, MRI systems have become increasingly complicated and expensive. There are two concepts in this proposal which set out to address the issues outlined above. The first is the optimization of high permittivity materials to improve image quality for a number of different clinical applications on a person-by-person basis. This requires a full understanding of the effects of these materials, the ability to predict and manufacture the optimum material, and acquiring the best possible data. The second “high-risk high-gain” concept is a totally new way of constructing MR resonators, which is based on conducting and reconfigurable plasmas. This concept can significantly simplify MR resonator design, can enable completely new types of MR experiment to be performed, and has intriguing possibilities to improve hybrid imaging systems such as combined positron emission tomography/MRI scanners.

LUMC press release about this ERC grant
ERC Advanced Grant - 2012 Christine Mummery: Title: Human Pluripotent Stem Cells: the new heart patient?
Acronym: STEMCARDIOVASC

Prof. Christine Mummery, PhD (link)
Department of Anatomy & Embryology

ERC Advanced Grant 2012 - panel LS7
EC contribution: EUR 2.500.000
Start date: 2013-11-01 - End date: 2018-10-31
Host institution: LUMC

Abstract:
The ability to generate pluripotent stem cells (iPSC) by reprogramming somatic tissues is arguably the greatest breakthrough in biomedical science of the last decade. The most inaccessible cells of the body can now be derived repeatedly from any individual. This could have a huge impact on understanding disease and the development of new therapeutic drugs but it will require a new level of sophistication in bioassays to create disease models and monitor disease phenotypes. The project I propose here will take up this challenge for the cardiovascular system, creating new human models of heart failure and vascular disease that presently do not exist. My group is uniquely positioned in Europe to realize these ambitions through more than a decade of research on cardiac and vascular cells from human embryonic stem cells and more recently hiPSC; its present location in Leiden University Medical Centre is optimal for fostering clinical links. My group is one of few worldwide that uses conventional homologous recombination in human PSCs. My aims here are (1) develop protocols for differentiating all cells of the heart (2) engineer synthetic and native human myocardium that models healthy tissue and common disease states and (3) generate sets of isogenic diseased hPSC to model pathogenesis. This will be realized by deriving lineage marked “rainbow coloured” reporter hPSC lines, introducing selected (immature) cardiovascular cells into engineered constructs and subjecting them to mechanical/biochemical stress factors like cyclic contraction and fluid flow that would normally induce maturation and disease. The constructs will support simultaneous measurement of functional tissue parameters and include hiPSC from relevant diseases, genetically or pharmacologically rescued and isogenic hESC with the corresponding gene mutations. These new “sick human heart” and “ diseased vessel” models and novel bioassays will significantly advance technology to have major impact on the field.

LUMC press release about this ERC grant
ERC Advanced Grant - 2012 Cock van de Velde: Title: Integrating cancer detection and SURgery Via molecular Imaging
Acronym: SURVIVE

Prof. Cock van de Velde, MD, PhD (link)
Department of Surgery

ERC Advanced Grant 2012 - panel LS7
EC contribution: EUR 2.487.600
Start date: 2013-11-01 - End date: 2018-10-31
Host institution: LUMC

Abstract:
The ambitious aim of this ERC-advanced grant proposal is to develop strategies that will connect cancer detection and surgery via tumor-specific molecular imaging techniques. This will lead to personalized patient-, or even tumor-specific treatment strategies. In addition, it will provide a tool for the selection of patients that, following preoperative (neoadjuvant) treatment, would benefit from additional (minimally invasive) surgery and identify patients who may be treated non-operatively. Fine-tuning the relation between tumor diagnosis, neoadjuvant treatment, preoperative planning and minimally invasive image-guided surgery will likely improve radical oncologic surgery while reducing surgical morbidity in cancer patients. The mechanistic aim of the proposal is to develop an integrated multimodal imaging strategy that will more accurately connect tumor biology with surgical resection approaches via the use of tumor-specific molecular imaging agents. The cornerstone of this approach is the unique clinical translation of tumor-targeted imaging agents that are both radioactive (diagnostic imaging) and fluorescently (surgical guidance) labeled. It is expected that the proposed multimodal imaging agents will allow for a significant improvement of both imaging and surgery strategies.

LUMC press release about this ERC grant
ERC Consolidator Grant – 2017 Jenny van der Steen: Title: Attempts to control the end of life in people with dementia: two-level approach to examine controversies
Acronym: CONT-END

Jenny van der Steen, PhD, Associate Professor (link)
Department of Public Health and Primary Care

ERC Consolidator Grant 2017 - panel SH3
EC contribution: EUR 1.988.972
Start date: TBC - End date: TBC
Host institution: LUMC

Abstract:
In dementia at the end of life, cognitive and physical decline imply that control is typically lost. CONT-END will examine control in the context of three emerging interventions which contain a controversial element of striving for control in the process of dying with dementia: advance care planning of the end of life, use of new technology to monitor symptoms when unable to self-report, and euthanasia. To perform outstanding research, the proposed research examines control at the level of clinical practice, but also at the level of end-of-life research practice. The latter provides ample opportunities for researchers to control the research process. That is, research designs are often flexible and we will study how flexibility impacts research in an emotionally charged area.
I will take an empirical mixed-methods approach to study the two practices in parallel. The work is organised in three related Work Packages around three research questions. (1) In a 6-country study, I will examine if and when people with dementia, family caregivers and physicians (900 respondents) find the interventions, shown on video, acceptable. (2) A cluster-randomised 3-armed controlled trial in 279 patients and their family caregivers assesses effects of two types of advance care planning differing in level of control (detailed advance treatment orders versus goal setting and coping based) on outcomes ranging from favourable to less favourable, and whether effects differ in subgroups. cases in which the technology is preferred or applied are observed. (3) Ethnographic fieldwork in two different end-of-life research practices and a Delphi study to synthesize CONT-END’s findings assess how researchers shape findings. This greatly improves the quality of CONT-END and provides the input to develop new methodology for improving research quality and integrity.

LUMC press release about this ERC grant
ERC Consolidator Grant - 2016 Susana Chuva de Sousa Lopes: Title: Oogenesis spotlighted: making mature human oocytes
Acronym: OVO-GROWTH

Susana Chuva de Sousa Lopes, PhD, Associate Professor (link)
Department of Anatomy & Embryology

ERC Consolidator Grant 2016 - panel LS7
EC contribution: EUR 2.000.000
Start date: 2017-07-01 - End date: 2022-06-30
Host institution: LUMC

Abstract:
Women who survive childhood cancer often fail to conceive because their eggs are damaged by (gonadotoxic) chemotherapy. A major breakthrough has been the possibility to cryopreserve cortical strips of their ovarian tissue for autologous transplantation later in life. This has led to over 80 successful pregnancies worldwide, one of the latest in the Netherlands. However, the risk of reintroducing cancer cells with the ovarian graft in patients with previous hematopoietic malignancies is too great and alternatives are needed. Here, I propose to build on my expertise in gametogenesis in mice and humans and perform a detailed study of the cellular networks and molecular pathways that control development and maturation of the oocyte within the human ovary. We have access and ethical approval for research on human foetal tissue and postnatal ovarian biopsies over a wide age range. I will use this rare material to systematically benchmark the transcriptional profile of cells in the human ovary (oocytes as well as somatic cells) during development and adulthood using Drop-seq, a novel cost-efficient single-cell technology that allows the profiling of thousands of cells in a matter of hours. Thereafter, we will apply mathematical algorithms to reveal cellular identities, developmental trajectories and signalling networks that control oogenesis. With this knowledge, I plan to engineer a human follicular niche creating a “mini-ovary” in vitro that could support the formation and maturation of the oocyte (using patient-specific cells) and to explore mechanisms of follicle maturation through a xenotransplantation mouse model. The cellular outcomes of these assays will be sequenced using Drop-seq and directly compared to their in vivo counterparts. Our approach will lead to more effective personalized-therapy for fertility preservation and contribute to the development of an in vitro mini-ovary organoid model to use in human reproductive toxicology and disease modelling.

LUMC press release about this ERC grant
ERC Consolidator Grant - 2016 Leendert Trouw: Title: The role of complement in the induction of autoimmunity against post-translationally modified proteins
Acronym: AUTOCOMPLEMENT

Leendert Trouw, PhD, Associate Professor (link)
Department of Rheumatology

ERC Consolidator Grant 2016 - panel LS7
EC contribution: EUR 1.999.802
Start date: 2017-09-01 - End date: 2022-08-31
Host institution: LUMC

Abstract:
In many prevalent autoimmune diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) autoantibodies are used as diagnostic and prognostic tools. Several of these autoantibodies target proteins that have been post-translationally modified (PTM). Examples of such modifications are citrullination and carbamylation. The success of B cell-targeted therapies in many auto-antibody positive diseases suggests that B cell mediated auto-immunity is playing a direct pathogenic role. Despite the wealth of information on the clinical associations of these anti-PTM protein antibodies as biomarkers we have currently no insight into why these antibodies are formed. Immunization studies reveal that PTM proteins can induce antibody responses even in the absence of exogenous adjuvant. The reason why these PTM proteins have ‘autoadjuvant’ properties that lead to a breach of tolerance is currently unknown. In this proposal, I hypothesise that the breach of tolerance towards PTM proteins is mediated by complement factors that bind directly to these PTM. Complement could be involved in the autoadjuvant property of PTM proteins as next to killing pathogens complement can also boost adaptive immune responses. I plan to unravel the importance of the complement–PTM protein interaction by answering these questions: 1) What is the physiological function of complement binding to PTM proteins? 2) Is the breach of tolerance towards PTM proteins influenced by complement? 3) Can the adjuvant function of PTM be used to increase vaccine efficacy and/or decrease autoreactivity? With AUTOCOMPLEMENT I will elucidate how PTM-reactive B cells receive ‘autoadjuvant’ signals. This insight will impact on patient care as we can now design strategies to either block unwanted ‘autoadjuvant’ signals to inhibit autoimmunity or to utilize ‘autoadjuvant’ signals to potentiate vaccination.

LUMC press release about this ERC grant
ERC Consolidator Grant - 2013 Haico van Attikum: Title: CHROMATIN-REPAIR-CODE: Hacking the chromatin code for DNA repair
Acronym: CHROMATINREPAIRCODE

Prof. Haico van Attikum, PhD (link)
Department of Human Genetics

ERC Consolidator Grant 2013 - panel LS2
EC contribution: EUR 1.999.575
Start date: 2014-03-01 - End date: 2019-02-28
Host institution: LUMC

Abstract:
Our cells receive tens of thousands of different DNA lesions per day. Failure to repair these lesions will lead to cell death, mutations and genome instability, which contribute to human diseases such as neurodegenerative disorders and cancer. Efficient recognition and repair of DNA damage, however, is complicated by the fact that genomic DNA is packaged, through histone and non-histone proteins, into a condensed structure called chromatin. The DNA repair machinery has to circumvent this barrier to gain access to the damaged DNA and repair the lesions. Our recent work suggests that chromatin-modifying enzymes (CME) help to overcome this barrier at sites of DNA damage. However, the identity of these CME, their mode of action and interconnections with DNA repair pathways remain largely enigmatic. The aim of this project is to systematically identify and characterize the CME that operate during DNA repair processes in both yeast and human cells. To reach this goal we will use a cross-disciplinary approach that combines novel and cutting-edge genomics approaches with bioinformatics, genetics, biochemistry and high-resolution microscopy. Epigenetics-IDentifier (Epi-ID) will be used as a tool to unveil novel CME, whereas RNAi-interference and genetic interaction mapping studies will pinpoint the CME that may potentially regulate repair of DNA damage. A series of functional assays will eventually characterize their role in distinct DNA repair pathways, focusing on those that counteract DNA strand breaks and replication stress. Together these studies will provide insight into how CME assist cells to repair DNA damage in chromatin and inform on the relevance of CME to maintain genome stability and counteract human diseases.

LUMC press release about this ERC grant
ERC Starting Grant - 2017 Thom Sharp: Title: Protein nano-patterning using DNA nanotechnology; control of surface-based immune system activation
Acronym: BioNanoPattern

Thom Sharp, PhD, Tenure track researcher (link)
Department of Molecular Cell Biology

ERC Starting Grant 2017 - panel LS9
EC contribution: EUR 1.499.850
Start date: 1-1-2018 - End date: 31-12-2022
Host institution: LUMC

Abstract:
Protein nanopatterning concerns the geometric arrangement of individual proteins with nanometre accuracy. It is becoming apparent that protein nanopatterns are essential for cellular function, and have roles in cell signalling and protection,phagocytosis and stem cell differentiation. Recent research indicates that our immune system is activated by nanopatterned antibody platforms, which initiate the classical Complement pathway by binding to the first component of Complement, the C1 complex. DNA nanotechnology can be used to form self-assembled nanoscale structures, which are ideal for use as templates to pattern proteins with specific geometries and nanometre accuracy. I propose to use DNA to nanopattern antigens and agonistic aptamers with defined geometry to study and control Complement pathway activation by the C1 complex. To develop and demonstrate the potential use of DNA to nanopattern proteins, the first aim of this proposal is to design DNA nanotemplates suitable for patterning antibody-binding sites. Antibodies and C1 will bind with specific geometry, and the relationship between antibody geometry and Complement activation will be assessed using novel liposome assays. Using DNA to mimic antigenic surfaces will enable high-resolution structure determination of DNA-antibody-C1 complexes, both in solution and on lipid bilayer surfaces, using phase plate cryo-electron microscopy to elucidate the structure-activation relationship of C1. The second aim of this proposal is to evolve agonistic aptamers that directly bind to and activate C1, and incorporate these into DNA nanotemplates. These nanopatterned aptamers will enable further study of C1 activation, and allow direct targeting of Complement activation to specific cells within a population of cell types to demonstrate targeted cell killing. This may open up new and highly efficient ways to activate our immune system in vivo, with potential for targeted anti-tumour immunotherapies.

LUMC press release about this ERC grant
ERC Starting Grant - 2016 Annette van der Helm-van Mil: Title: Rheumatoid Arthritis Caught Early: investigating biological mechanisms preceding chronification of joint inflammation to identify patients prior to presentation of classic chronic arthritis
Acronym: RACE

Prof. Annette van der Helm – van Mil, MD, PhD (link)
Department of Rheumatology

ERC Starting Grant 2016 - panel LS7
EC contribution: EUR 1.500.000
Start date: 2017-10-01 - End date: 2022-09-30
Host institution: LUMC

Abstract:
Rheumatoid Arthritis (RA) causes long lasting disability. At the time of clinically evident arthritis and diagnosis, the disease is already persisting, requiring long-term suppressive treatment. My overarching aim is to prevent chronic arthritis and RA by inhibiting the evolving auto-immune response in a pre-arthritis phase. Currently, identification of RA-patients before the classic presentation with clinically evident chronic arthritis is beyond the state of the art. I here aim to achieve this early recognition by increasing the mechanistic understanding of pre-arthritis phases. I intend to study RA-specific auto-immune responses at the cellular and humoral level as well as markers reflecting local and systemic inflammation. These aspects are selected based on my world-wide validated rule to predict RA-development in early arthritis and on recent work on progression from Clinically Suspect Arthralgia (CSA) to clinical arthritis. This project is now finally feasible, thanks to unique ‘pre-RA’ cohorts and cross-boundary preparatory work done with basic scientists, clinicians and engineers. My research concept is to integrate the products of separate trajectories in a longitudinal study and translate it to the clinic. Patients with CSA will be studied serially in time. Using validated methods and novel techniques and insights we will: delineate molecular and predictive features of RA-specific auto-antibodies and auto-antibody secreting B-cells, identify improved markers of systemic inflammation and test and validate a computer-aided image analysis system to detect subclinical joint inflammation on MRI. Serial data will be combined to reveal interactions between markers and time relationships. Lastly a prediction model identifying imminent RA will be developed. The forefront position of my group allows national and international validation. Together, this multidisciplinary and intersectorial project will open new horizons for preventive, targeted interventions.

LUMC press release about this ERC grant
ERC Starting Grant - 2016 Daniel Pijnappels: Title: Biological auto-detection and termination of heart rhythm disturbances
Acronym: Bio-ICD

Daniel Pijnappels, PhD, Associate Professor (link)
Department of Cardiology

ERC Starting Grant 2016 - panel LS7
EC contribution: EUR 1.485.028
Start date: 2017-03-01 - End date: 2022-02-28
Host institution: LUMC

Abstract:
Imagine a heart that could no longer suffer from life-threatening rhythm disturbances, and not because of pills or traumatizing electroshocks from an Implantable Cardioverter Defibrillator (ICD) device. Instead, this heart has become able to rapidly detect & terminate these malignant arrhythmias fully on its own, after gene transfer. In order to explore this novel concept of biological auto-detection & termination of arrhythmias, we will investigate how forced expression of particular engineered proteins could i) allow cardiac tissue to become a detector of arrhythmias through rapid sensing of acute physiological changes upon their initiation. And how after detection, ii) this cardiac tissue (now as effector), could terminate the arrhythmia by generating a painless electroshock through these proteins. To this purpose, my team will first explore the requirements for such detection & termination by studying arrhythmia initiation and termination in rat models of atrial & ventricular arrhythmias using optical probes and light-gated ion channels. These insights will guide computer-based screening of proteins to identify those properties allowing effective arrhythmia detection & termination. These data will be used for rational engineering of the proteins with the desired properties, followed by their forced expression in cardiac cells and slices to assess anti-arrhythmic potential & safety. Promising proteins will be expressed in whole hearts to study their anti-arrhythmic effects and mechanisms, after which the most effective ones will be studied in awake rats. This unexplored concept of self-resetting an acutely disturbed physiological state by establishing a biological detector-effector system may yield unique insight into arrhythmia management. Hence, this could provide distinctively innovative therapeutic rationales in which a diseased organ begets its own remedy, e.g. a Biologically-Integrated Cardiac Defibrillator (Bio-ICD).

LUMC press release about this ERC grant
ERC Starting Grant - 2014 Richard Davis: Title: Stem Cells for Cardiac Arrhythmia Risk Assessment
Acronym: STEMCARDIORISK

Richard Davis, PhD, Associate Professor (link)
Department of Anatomy & Embryology

ERC Starting Grant 2014 - panel LS7
EC contribution: EUR 1.500.000
Start date: 2015-11-01 - End date: 2020-10-31
Host institution: LUMC

Abstract:
Among the most significant conceptual changes in stem cell biology of the past decade has been the use of human pluripotent stem cells (hPSCs) for disease modelling and drug development rather than solely as therapeutics. One area of major interest in this context is that of arrhythmic disorders of the heart. Cardiac arrhythmias are a leading cause of death among young people, with inherited forms affecting as many as 1 in 2000. Even more prevalent are acquired arrhythmias due to adverse responses to medication. These too have a significant heritable component. Although hundreds of mutations have been associated with both forms of arrhythmia, two outstanding issues remain: (i) it is difficult to prove the identified mutation is causal, and (ii) large differences in disease severity are seen even among patients with the same primary mutation. To date hPSC models of arrhythmogenic diseases exhibit the characteristic electrophysiological features of the respective disorders; however lack of appropriate controls and inherent variability between hPSC lines means that it is still unclear how well these models reflect the genotype-phenotype relationship. This proposal will combine hPSC disease modelling with recent advances in gene-editing, plus the wealth of genomic data associating genetic variants to disease phenotypes, to develop unique approaches that will 1) establish the sensitivity of these models and; 2) provide more accurate functional assessment of the contribution of individual variants to congenital and acquired arrhythmias. I believe that by creating panels of isogenic PSC lines differing exclusively at candidate genetic loci we can (i) predict the pathogenicity of variants; (ii) shed light on the mechanism underlying the disease phenotype, and (iii) improve individual risk stratification and patient-specific pharmacotherapy. This study will also offer a first entry into interpreting GWAS and capitalising on the value of the human genome sequencing projects.

LUMC press release about this ERC grant
ERC Starting Grant - 2012 Fijs van Leeuwen: Title: Hybrid imaging agents for the illumination of peripheral nerve structures
Acronym: ILLUMINATING NERVES

Fijs van Leeuwen, PhD, Associate Professor (link)
Department of Radiology

ERC Starting Grant 2012 - panel PE5
EC contribution: EUR 1.498.800
Start date: 2012-08-01 - End date: 2017-07-31
Host institution: LUMC

Abstract:
The aim of the ILLUMINATING NERVES project is to develop and synthesize new imaging agents that eventually can be used for surgical guidance around delicate nerve structures. The applicants research group already has made a major contribution to the clinical field of surgical guidance by introducing a concept wherein a multimodal/hybrid, imaging agent is used to provide fully integrated preoperative 3D imaging, surgical procedure planning, and real-time surgical fluorescence guidance. Illumination of delicate anatomical structures like nerves will have a direct influence on the quality of life of patients and as such creates a new window of opportunities for surgical guidance and for the chemical development of hybrid imaging agents. To illuminate both somatic and autonomic peripheral nerves, imaging agents will be developed that bind to receptors on myelinating Schwann cells and/or accumulate in neurons. These different targeting concepts dictate the use of different scaffold molecules varying from targeted antibodies to modified neurotoxin proteins that act as bionanoparticles and viral capsids, each scaffold demanding different synthetic routes for functionalization. For this particular application, the visualization of small nerves, especially the fluorescent imaging contrast has to increase compared to conventional imaging agents. The applicant’s multidisciplinary track record the chemical and (bio)medical field, combined with his proven ability to bridge the gap between bench and bedside aids in the successful integration of synthetic chemical strategies with biomedical assays and in vitro/in vivo validation studies. Although possibly providing interesting imaging agent candidates suitable for optimization towards a future clinical translation, the project will mainly generate fundamental insight in the types of (hybrid) imaging agents that have potential for the surgical illumination of peripheral nerves.

LUMC press release about this ERC grant

In 2015, Fijs van Leeuwen also received an ERC Proof of Concept Grant (acronym MY NERVE), to explore the commercial/societal potential of the project above
ERC Starting Grant - 2012 Alfred Vertegaal: Title: Cracking the SUMO Signalling Code
Acronym: DECODINGSUMO

Alfred Vertegaal, PhD, Associate Professor (link)
Department of Molecular Cell Biology

ERC Starting Grant 2012 - panel LS1
EC contribution: EUR 1.517.698
Start date: 2013-01-01 - End date: 2017-12-31
Host institution: LUMC

Abstract:
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.

LUMC press release about this ERC grant

Key publications from this ERC project

A comprehensive compilation of SUMO proteomics. Hendriks I.A. and Vertegaal A.C.O. Nature Reviews Molecular Cell Biology 2016; 17: 581–595. Link

System-wide identification of wild-type SUMO-2 conjugation sites. Hendriks I.A., D’Souza R.C., Chang J.G., Mann M. and Vertegaal A.C.O. Nature Communications 2015; 6: 7289. Link

Uncovering global SUMOylation signaling networks in a site-specific manner. Hendriks I.A., D'Souza R.C., Yang B., Verlaan-de Vries M., Mann M. and Vertegaal A.C.O. Nature Structural & Molecular Biology 2014; 21: 927–936. Link
ERC Starting Grant - 2011 Huib Ovaa *: Title: Decoding the ubiquitin code
Acronym: UBICODE

Prof. Huib Ovaa, PhD (link)
Department of Chemical Immunology

ERC Starting Grant 2011 - panel LS1
EC contribution: EUR 1.498.240
Start date: 2011-11-01 - End date: 2016-10-31
Host institution: Netherlands Cancer Institute was the initial Host Institution of this grant, the PI and his ERC project moved to LUMC in 2016.

Abstract:
Ubiquitin (Ub) is a 76 amino acid protein that is commonly found in isopeptide linkage to a lysine residue of a target protein. This post-translational modification controls most cellular processes, including DNA repair, trafficking and protein degradation. Ubiquitin conjugation onto any of its 7 own lysine residues or onto its N-terminus results in a large number of differently linked polymers; the shape, charge and size of which determine how they interact with ubiquitin binding domains (UBDs). Binding to proteins containing such domains triggers further events that determine the fate of a Ub-tagged substrate in subsequent biochemical events in a Ub chain topology dependent manner. Malfunction of these signal transduction events contributes to the pathology of human disease. Although all Ub linkages are found in cells and all likely have specific functions, only few of them have been intensively studied so far as most linkages cannot be generated biochemically.
This project will investigate how Ub linkages are recognized by UBDs to transduce cellular signals in a chain specific manner, including all linkages with all their possible topoisomers. This information will then be used to generate pharmacological modulators aimed at interfering with specific UBD-mediated signal transduction events.

Key publications from this ERC project

Synthetic and semi-synthetic strategies to study ubiquitin signaling. Van Tilburg G.B., Elhebieshy A.F. and Ovaa H. Current Opinion in Structural Biology 2016; 38: 92-101. Link

Molecular basis of Lys11-polyubiquitin specificity in the deubiquitinase Cezanne. Mevissen T.E., Kulathu Y., Mulder M.P., Geurink P.P., Maslen S.L., Gersch M., Eliott P.R., Burke J.E., van Tol B.D., Akutsu M., El Oualid F., Kawasaki M., Freund S.M., Ovaa H. and Komander D. Nature 2016; 538: 402-405. Link

On terminal alkynes that can react with active-site cysteine nucleophiles in proteases. Ekkebus R., van Kasteren S.I., Kulathu Y., Scholten A., Berlin I., Geurink P.P., de Jong A., Goerdayal S., Neefjes J., Heck A.J., Komander D. and Ovaa H. Journal of the American Chemical Society 2013; 135: 2867-70. Link
ERC Starting Grant - 2009 Gijs van den Brink *: Title: Morphostasis of the intestinal mucosa and it's deregulation in cancer and inflammation
Acronym: MORPHOSTASIS

Gijs van den Brink, PhD, Associate Professor
Department of Gastroenterology and Hepatology
Current affiliation: Academic Medical Center Amsterdam

ERC Starting Grant 2009 - panel LS4
EC contribution: EUR 1.524.462
Start date: 2009-10-01 - End date: 2014-09-30
Host institution: LUMC was the initial Host Institution of this grant, the PI and his ERC project moved to Academic Medical Center Amsterdam in 2010

Abstract:
Stem cells at the base of the intestinal crypts are in a dynamic equilibrium with their differentiated derivatives. Homeostatic equilibria depend on the presence of negative feedback loops. The role of the Wnt signaling pathway as a driver of epithelial stem cell self renewal and proliferation in the intestine has been relatively well characterized. Much less is known about the negative feedback signals that must exist to control stem cell behavior and the way these may be deregulated in disease. We found that Indian hedgehog is secreted by differentiated intestinal epithelial cells and acts as a negative feedback signal. Hedgehog signaling acts as a break on Wnt signaling in intestinal precursor cells via a secondary signal in the mesenchyme. We will use conditional mutant mice, our large biobank of patient materials and in vitro experiments to further characterize the signals involved in this feedback loop. Our objective is to study the role of this epithelial mesenchymal signaling circuit in the normal intestine and examine the way it is deregulated in intestinal cancer development and inflammation.
ERC Starting Grant - 2007 Marcel Tijsterman *: Title: Developmental and Genetic Analysis of DNA Double-Strand Break Repair
Acronym: DSBrepair

Prof. Marcel Tijsterman, PhD (link)
Department of Human Genetics

ERC Starting Grant 2007 - panel LS2
EC contribution: EUR 1.060.000
Start date: 2008-05-01 - End date: 2014-04-30
Host institution: Hubrecht Institute at the Royal Netherlands Academy of Arts and Sciences (KNAW) was the initial Host Institution of this grant, the PI and his ERC project moved to LUMC in 2009.

Abstract:
The DNA within our cells is constantly being damaged by both environmental and endogenous agents; of the many forms of DNA damage, the DNA double-strand break (DSB) is considered to be most dangerous. Correct processing of DSBs is not only essential for maintaining genomic integrity but is also required in specific biological processes, such as meiotic recombination and V(D)J recombination, in which DNA breaks are deliberately generated. In animals, defects in the proper response to DSBs can thus have different outcomes: cancer predisposition, embryonic lethality, or compromised immunity. Many genes that play a role in the processing of DSBs have been identified over the past decades, mainly by cloning genes that are responsible for specific human genomic instability or immune deficiency syndromes, and by genetic approaches using unicellular eukaryotes and rodent cell lines. It is, however, evident that many components required in higher eukaryotes are not yet known and the identification of those will be a major challenge for future research. Here, we will for the first time systematically test all genes encoded by an animals genome directly for their involvement in the cellular response to DSB in both somatic and germline tissues: we will use our recently developed transgenic animal models (C. elegans) that visualizes repair of a single localized genomic DNA break in genome wide RNAi screenings to identify (and then characterize) the complement of genes that are required to keep our genome stable, and when mutated can predispose humans to cancer. In parallel, we will study the cellular response to single DNA breaks that are artificially generated during different stages of gametogenesis, as well as address the developmental consequences of DSB induction during the earliest stages of embryonic development – an almost completely unexplored area in the field of genome instability and DNA damage responses.

Key publications from this ERC project

Polymerase theta-mediated end joining of replication-associated DNA breaks in C. elegans. Roerink S.F., van Schende R. and Tijsterman M. Genome Research 2014; 24: 954-62. Link

A Polymerase Theta-dependent repair pathway suppresses extensive genomic instability at endogenous G4 DNA sites. Koole W., van Schendel R., Karambelas A., van Heteren J.T., Okihara K.L. and Tijsterman M. Nature Communications 2014; 5: 3216. Link

COM-1 promotes homologous recombination during Caenorhabditis elegans meiosis by antagonizing Ku-mediated non-homologous end joining. Lemmens B.B., Johnson N.M. and Tijsterman M. PLOS Genetics 2013; 9: e1003276. Link
ERC Proof of Concept Grant - 2017 Fijs van Leeuwen: Title: Tracers for targeting nerves in the autonomic nervous system
Acronym: AUTO NERVE

Fijs van Leeuwen, PhD, Associate Professor (link)
Department of Radiology

ERC Proof of Concept Grant 2017
EC contribution: EUR 140.000
Start date: TBC - End date: TBC
Host institution: LUMC

Abstract:
As a common disease in western men, prostate cancer is a major driver for the billion-euro robotic surgery and laparoscopic devices markets. In the surgical management of prostate cancer patients, next to the tumor resection accuracy, the surgeon’s ability to preserve the nerve-network and prevent erectile dysfunction and urinary incontinence, is key. As these nerves are not visible by eye, image guided surgery approaches aimed at nerve-sparing demand the clinical availability of nerve-specific fluorescence tracers. Hereby it is expected that the ability to visualize peripheral nerves promotes nerve sparing opportunities and opens up new commercial-avenues for companies involved in the surgical market. Previously the ILLUMINATING NERVES ERC-StG yielded a myelin targeted lead-compound that was made suitable for imaging somatic nerves (MY NERVE ERC-PoC project; patent pending). This tracer, however, does not allow for imaging of the autonomic nerves. For autonomic nerves we have now shown, within the same ERC-StG, that an alternative protein can be explored as an imaging target. The aim of this AUTO NERVE ERC-PoC project is to also convert the new lead-compound into a fluorescence tracer. Systematic fine tuning of this lead will optimize the structure-activity relation, IP-position, and cost of production. Together with clinical good manufacturing practice (GMP) compliance, this provides a solid basis for future commercialization. These tracer development benefit from parallel engineering of fluorescence guidance modalities together with the leading industrial partners e.g. Intuitive Surgical Inc. and KARL STORZ Endoskope GmbH. Modification of their fluorescence laparoscopes to allow simultaneous use of different dyes in the clinic, supports the implementation of novel fluorescent nerve tracers in clinical routine. Feedback from end-users ensures the final product tis tailored towards clinical demand and helps abolish surgical side effects as result of nerve damage.

Fijs van Leeuwen received an ERC Starting Grant (acronym ILLUMINATING NERVES) in 2012. In 2015, he received a first ERC Proof of Concept Grant (acronym MY NERVE). The objective of ERC Proof of Concept Grants is to explore the commercial/societal potential of results from initial ERC projects.
ERC Proof of Concept Grant - 2015 Fijs van Leeuwen: Title: Translation of a fluorescent MYelin specific peripheral NERVE tracer
Acronym: MY NERVE

Fijs van Leeuwen, PhD, Associate Professor (link)
Department of Radiology

ERC Proof of Concept Grant 2015
EC contribution: EUR 140.000
Start date: 2016-03-01 - End date: 2017-08-31
Host institution: LUMC

Abstract:
Tracers that enable imaging of peripheral nerve structures have the potential to reduce the occurrence of perioperative peripheral nerve injury. Hence, through such a fluorescence-guided surgery technique morbidity and related follow up costs may be reduced and the quality of life of patients can be improved. The ability to visualize peripheral nerves also creates nerve-sparing opportunities for surgeons and opens up new commercial-avenues for companies involved in the surgical market. The aim of the MY NERVE ERC-PoC project is to strengthen the IP-position and aid the translation of a new nerve specific tracer. The most promising tracer derived from the ILLUMINATING NERVES ERC-StG, serves as the lead compound in this application. Systematic fine-tuning of this lead will help optimization of the structure-activity relation. Together with compatibility with clinical good manufacturing practice (GMP) production requirements this helps provide a solid basis for future commercialization. The applicant has a multidisciplinary track record in the chemical and (bio)medical field. By driving the clinical translation of new imaging tracers, his research group already has made significant contributions to the field of fluorescence guided surgery. Combined with legal support regarding IP-position, feedback from end-users (surgeons), and industrial partners with a global leading position in the surgical market, this background will ensure a translational approach. Ultimately, bridging the gap between synthetic chemical developments and the clinical demand for fluorescent tracers should help accomplish patient benefit.

In 2012, Fijs van Leeuwen received an ERC Starting Grant (acronym ILLUMINATING NERVES). The objective of the Proof of Concept Grant above is to explore the commercial/societal potential of his initial ERC project.