ERC Advanced Grant 2021 – Maria Yazdanbakhsh - Reversing vaccine hypo-responsiveness

REVERSE

Prof. Maria Yazdanbakhsh, PhD

Department of Parasitology

• ERC Advanced Grant 2021 –
• EC contribution: EUR 2,372,681
• Start date: TBC – End date: TBC

Abstract

will follow shortly.

ERC Advanced Grant 2020 - Andrew Webb - Portable, accessible and sustainable magnetic resonance Andrew Webb

PASMAR

Prof. Andrew Webb, PhD

Department of Radiology

• ERC Advanced Grant 2020 – panel LS7
• EC contribution: EUR 2,493,715
• Start date: 01-09-2021 – End date: 31-08-2026

Abstract

Magnetic resonance imaging (MRI) provides high-definition diagnostic imaging. However, it’s very expensive and requires skilled maintenance and highly trained technicians. The EU-funded PASMAR project aims to provide MRI systems that will enable medical screening as part of an affordable, sustainable and accessible platform for the developing world. The objective is to design new types of low-cost low-field systems for specific clinical applications and overcome the main challenge of much lower MRI signals. These specialised systems can be used for adult/paediatric brain, orthopaedics and lung/spine scanning, taking advantage of the flexibility of permanent magnet arrays with new geometries, targeted for specific organs, and using open-source design to allow local maintenance and repair.

Andrew Webb already received an ERC Advanced Grant in 2014.

ERC Advanced Grant 2019 – Rene Toes - Targeting auto-reactive B-cells by vaccination to cure human auto-immune disease

Target to B-Cure

Prof. Rene Toes, PhD 

Department of Rheumatology

• ERC Advanced Grant 2019 - panel LS7
• EC contribution: EUR 2,500,000
• Start date: 01-01-2021 - End date: 31-12-2025

Abstract

Most incurable human autoimmune diseases are chronic conditions characterized by the presence of autoantibodies. Elimination of the autoreactive B-cells are not presently feasible due to a lack of specific markers. The EU-funded Target to B-cure project aims to develop a vaccine that will allow specific long-lasting depletion of autoreactive B-cells. Using autoimmune rheumatoid arthritis (RA) as a model, it will study the RA specific autoimmune response. Researchers will identify autoreactive B-cells and the B cell receptor (BCR) repertoire at several stages of the disease to determine the potency of the non-germline-encoded mutations in BCRs as antigens amenable to T-cell recognition and vaccination. Finally, the project will design patient-tailored vaccines and perform a phase I trial to determine the feasibility of depleting disease-causing B-cells.

ERC Advanced Grant 2018 – Johanna Meijer - The circadian clock in day-active species: preserving our health in modern society

DiurnalHealth

Prof. Johanna Meijer, PhD

Department of Cell and Chemical Biology

• EC contribution: EUR 2,233,251
• Start date: 01-09-2019 - End date: 31-08-2024

Abstract

Due to a significant increase in the use of artificial light in our 24h economy, the biological clocks of all living organisms, including humans, are severely disrupted. Many severe health disorders are consequences of clock disruption such as diabetes, sleep/mood disorders, cardiovascular disease, and immune dysfunction. The central timekeeper in mammals is the suprachiasmatic nucleus (SCN), and the mechanisms by which light disrupts integrity of the SCN has been well investigated in nocturnal species. In contrast, mechanisms of clock disruption in humans and other diurnal (day-active) species remain poorly defined. I have evidence that the mechanisms that drive SCN function are fundamentally different between nocturnal species and diurnal species. This defines my aim to restore proper clock function in diurnal species, including humans. To test this, in Objective 1 we will identify similarities and differences between nocturnal and diurnal clocks with respect to their i) response to light, ii) neuronal synchronization, iii) output, and iv) response to physical activity. Based on these findings, in Objective 2 we will develop novel strategies to manipulate and restore clock function in diurnal species. These objectives will be achieved using novel, state-of-the-art chronobiology methods including in vivo electrophysiology and Ca2+ and bioluminescence reporters—all in freely behaving day-active animals, as well as in slice preparations containing the SCN. For studies on the human SCN we record with 7-Tesla fMRI. This proposal will help establish a new basis for chronobiology with respect to the most suitable models for studying translational applications. The results will yield immediate benefits in terms of manipulating biological clock function among vulnerable populations in modern society, particularly the elderly, patients in intensive care, and shift workers.

ERC Consolidator Grant 2021 – Martijn Luijsterburg - Mechanisms at the interface of DNA damage repair and transcription

STOP-FIX-GO

Martijn Luijsterburg, PhD, Associate Professor (pasfoto invoegen?)

Department of Human Genetics

• ERC Consolidator Grant 2021 – panel LS1
• EC contribution: 1,999,764 euro
• Start date: TBC; End date: TBC

Abstract: will follow shortly.

ERC Consolidator Grant 2021 – Daniel Pijnappels - Translational optoelectronic control of cardiac rhythm in atrial fibrillation

TransRhythm

Prof. Daniel Pijnappels, PhD (pasfoto invoegen?)

Department of Cardiology

• ERC Consolidator Grant 2021 – panel LS7
• EC contribution: 1,999,999 euro
• Start date: TBC; End date: TBC

Abstract: will follow shortly.

Daniel Pijnappels already received an ERC Starting Grant in 2016.

ERC Consolidator Grant 2020 – Milena Bellin - Human mini hearts: looking for culprits and victims in cardiac disease

Mini-HEART

Milena Bellin, PhD, Associate Professor (pasfoto invoegen?)

Department of Anatomy & Embryology

• ERC Consolidator Grant 2020 – panel LS4
• EC contribution: 2,000,000 euro
• Start date: 01 September 2021; End date: 31 August 2026
• We are hosting this research together with the University of Padua

Abstract

Cardiac disease causes morbidity and mortality as frequently as cancer. Predicting cardiac arrhythmia and cardiac failure, understanding multicellular (patho)physiological mechanisms, and devising new treatments represent unmet needs in the field. Human induced pluripotent stem cells (hiPSC) could revolutionise the way we study human disease but unfortunately, they still fall short in recapitulating variable phenotypes and complex cardiovascular diseases. This is partly due to functional immaturity of hiPSC-derived cardiac tissues, shortage of methods for accurate functional analysis and inability to identify cell-type specific contributions to disease pathology. I will address these challenges in Mini-HEART. We recently assembled novel three-dimensional multi-cellular cardiac microtissues as an important step towards full maturation and used these to demonstrate that cardiac disease mutations might directly affect non-myocyte cardiac cells. However, application of hiPSC microtissues to precision medicine remains to emerge. Using a multidisciplinary approach, I will combine isogenic hiPSC, their differentiation into distinct cell types of the heart, multifaceted biophysical assays, and tissue engineering to prove cell-type causality of disease and identify new molecules targeting the culprit cells to rescue the disease phenotype. I plan to use our unique complex hiPSC-cardiac microtissue to

1. identify and synthetically enhance maturation mechanisms;
2. reveal late arrhythmic and fibrotic phenotypes;
3. dissect cell-type specific contributions to complex cardiac diseases, including the role of macrophages and sympathetic nerves;
4. test two therapeutic strategies based on drug-tailoring and gene editing, to modulate the disease phenotype.

Together, Mini-HEART will create new opportunities for designing novel biomedical tools to
i) capture phenotypic changes,
ii) reveal (patho)physiological mechanisms and ii) develop new therapeutic approaches for heart disease.

ERC Consolidator Grant 2017 – Jenny van der Steen - Attempts to control the end of life in people with dementia: two-level approach to examine controversies

CONT-END

Jenny van der Steen, PhD, Associate Professor

Department of Public Health and Primary Care

• ERC Consolidator Grant 2017 - panel SH3
• EC contribution: EUR 1,988,972
• Start date: 2018-12-01- End date: 2023-11-30

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.

ERC Consolidator Grant 2016 – Susana Chuva de Sousa Lopes - Oogenesis spotlighted: making mature human oocytes

OVO-GROWTH

Susana Chuva de Sousa Lopes, PhD, Associate Professor (pasfoto invoegen?)

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

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.

ERC Consolidator Grant 2016 – Leendert Trouw - The role of complement in the induction of autoimmunity against post-translationally modified proteins

AUTOCOMPLEMENT

Leendert Trouw, PhD, Associate Professor

Department of Immunology

• ERC Consolidator Grant 2016 - panel LS7
• EC contribution: EUR 1,999,802
• Start date: 2017-09-01 - End date: 2022-08-31

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.

ERC Starting Grant 2020 – Baoxu Pang - The darker side of the genome: systemically studying the biology of repressive elements - silencers - in the human genome

Silencer

Baoxu Pang, PhD, Assistant Professor 
Department of Cell and Chemical Biology

• ERC Starting Grant 2020 - panel LS2
• EC contribution: EUR 1,750,000
• Start date: 01-02-2021 - End date: 31-01-2026

Abstract

Less than 1.5% of the human genome contains protein coding information of the estimated 25,000 genes. The rest of the non-coding genome includes many regulatory elements that control the spatial and temporal transcription of genes. With the help of the non-coding regulatory elements, the diverse cell types and tissues of a complex human body could be derived from the combinational expression of a limited number of genes from the same copy of the genome. Most regulatory elements (REs) have been characterized extensively, e.g. promoters, enhancers and insulators. These REs have been implicated to play very important roles in cell physiology, tissue development and disease onsets. Surprisingly, one class of REs—silencers—which repress the transcription of genes, have not been systematically characterized and studied. I have developed a lentiviral system to systematically identify functional silencer elements. In the small-scale proof-of-principle experiments, by focusing on the transcriptional factor (TF) accessible DNA sequences, I showed that this system is robust to identify novel and bona fide silencers, which could be validated using complementary functional assays such as luciferase and CRISPR knockout assays. In this proposed research plan, I aim to identify silencers in an unbiased way, rather than focusing on TF accessible regions, to have a more general understanding of the biology of silencers. Based on the unbiased identification of silencers, I aim to identify a general pattern of epigenetic modifications of silencers, unique combination of sequence motifs, responsible regulatory TFs, biological pathways that are regulated by silencers, diseases that might be related to mutations in silencers, and finally better manipulation strategies of silencers.

ERC Starting Grant 2019 – Noel de Miranda - RAtional design of canceR ImmunoTherapY: one size does not fit all

RARITY

Noel de Miranda, PhD
Department of Pathology

• ERC Starting Grant 2019 - panel LS7
• EC contribution: EUR 1,499,795
• Start date: 01-12-2019 - End date: 30-11-2024

Abstract

Checkpoint blockade immunotherapies have revolutionized cancer treatment. However, this immunotherapy only benefits a minority of patients (< 15%), mainly those diagnosed with cancers having many mutations. Furthermore, checkpoint blockade therapy does not selectively activate cancer-reactive T cells. RARITY responds to these shortcomings, aiming to provide innovative solutions for the development of effective immunotherapies for patients who do not benefit from current treatments. The ground-breaking preliminary data included in this application demonstrates that cancer-reactive T cells can be naturally present in so-called non-immunogenic cancers and that they acquire distinctive phenotypes. RARITY will apply state-of-the-art technologies to fingerprint these phenotypes. This will allow the isolation of cancer-reactive T cells from tumour tissues and their employment as highly-effective therapies. Therapeutic vaccination with cancer antigens can also be used to induce T cell responses in patients where natural activation of cancer-specific T cells is not detectable. However, the applicability of vaccination is compromised by the lack of specific targets, particularly in malignancies with few mutations. RARITY will address this problem by deploying a novel class of cancer antigens. An unprecedented screening of non-exomic genomic regions will be done to detect unannotated proteins that arise from de novo transcription and translation events. These proteins can then be targeted by personalized immunotherapies. Finally, thought-provoking findings included in RARITY suggest that immune cell subsets other than T cells play a major role in anti-tumour immune responses. These subsets need to be fully inventoried and categorised so that complementary strategies to T cell immunotherapies can be developed. RARITY will do so by conducting multidimensional analysis of cancer microenvironments using imaging mass cytometry and ex vivo modulation of immune responses.

ERC Starting Grant 2017 – Thom Sharp - Protein nano-patterning using DNA nanotechnology; control of surface-based immune system activation

BioNanoPattern

Thom Sharp, PhD, Tenure track researcher

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

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.

ERC Starting Grant 2016 – Annette van der Helm van Mil - Rheumatoid Arthritis Caught Early: investigating biological mechanisms preceding chronification of joint inflammation to identify patients prior to presentation of classic chronic arthritis

RACE

Prof. Annette van der Helm – van Mil, MD, PhD 
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

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.

ERC Starting Grant 2016 – Daniel Pijnappels - Biological auto-detection and termination of heart rhythm disturbances

Bio-ICD

Daniel Pijnappels, PhD, Associate Professor
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

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).