PROteoMIcS in cErebral Small Vessel Disease to define molecular subtypes in stroke and dementia
Prof. G.J. Biessels, UMC Utrecht, Dr Y.M. Ruigrok, UMC Utrecht, Dr B.M. Tijms, Amsterdam UMC
Cerebral small vessel disease (SVD) are an important cause of strokes and dementia. In old age, almost everyone has SVD on brain scans, but there are major interindividual differences. One person may have a lot of SVD, the other little, one may have marked SVD-related complaints, the other none or hardly any. This can make the diagnosis difficult. Better treatment is also urgently needed.
The concept of the PROMISE-SVD research project is that differences in SVD between people are explained by differences in underlying disease processes, which we can recognize by measuring protein profiles in the blood using new techniques. We expect to find different SVD subgroups, with differences in hereditary predisposition, scan abnormalities and clinical consequences. The protein profiles will also provide indications of causes and that is relevant for treatment. The results thus contribute to the development of a better, personalized approach to SVD.
A Chemical Approach for Immune Inhibitory Receptor Agonists
Prof. L. Meyaard, UMC Utrecht, Prof. S.I. van Kasteren, Leiden University, Dr M. van der Vlist, UMC Utrecht
Immune-mediated inflammatory diseases (IMIDs) affect 5–7% of the Western population. IMIDs comprise a chronic, clinically diverse group of conditions and many patients still lack good treatment options. Stimulation of immune checkpoint receptors is a novel strategy to suppress inflammation in IMIDs. Development of therapeutic checkpoint stimulators to suppress inflammation is challenging. In contrast to most receptors, scientists do not understand how the concentration or binding strength of natural stimulators affects these checkpoints. With a recently developed microscopy technique and a unique set of checkpoint receptor binders, we will study the detailed characteristics of binder:receptor interaction that determine immune checkpoint function. With this knowledge, we aim to chemically synthesise checkpoint stimulators for future therapeutic use in inflammatory disease.
Cholesterol handling in lysosomes and beyond: The ins and outs (ODYSSEUS)
Prof. N. Zelcer, Amsterdam UMC, Dr J.C. Wolters, University Medical Center Groningen
Cholesterol is essential for life, but when our body does not deal with cholesterol properly this can lead to the development of many diseases, including for example fatty liver disease, cancer, and neurodegeneration. The liver is the central organ that controls cholesterol homeostasis in the body, and in this project, ODYSSEUS, the researchers will study how the liver deals with cholesterol. They will investigate a compartment in the liver cells that is called the lysosome, which can be viewed as a cholesterol “central distribution center”. Cholesterol must exist the lysosome and reach different places in the cell, but how this happens is not well understood. Studying these processes and identifying the “roads” that cholesterol takes out of the lysosome is the focus of this project. By understanding how these processes normally take place the researchers aim to find interventions to treat cholesterol-related diseases in the liver and beyond.
Safe2(H)ear: Towards safe and precise drug delivery to the inner ear
Prof. R.J.E. Pennings, Radboudumc, Prof. D. Fernandez Rivas, University of Twente
Prof. H. Maier, Medizinische Hochschule Hannover (Germany), Dr E. de Vrieze, Radboudumc
Nearly 20% of the global population suffers from hearing loss. Hearing aids can reduce the burden of hearing loss, but treatments to prevent hearing loss, or restore normal hearing, are not yet available. The major challenge in the development of novel treatments for hearing loss is the inaccessibility of the hearing organ, the cochlea. Delivering even a tiny amount of drug solution can damage the fragile cells within the cochlea. In the Safe2(H)ear project, we will study the boundaries between the cochlea and the easier to reach middle ear. We will use these insights to investigate how drugs can be safely delivered to the cochlea. We will also develop animal free model systems to accelerate research into novel treatments for hearing loss.
Resolving Endo-Lysosomal Dependencies and Targets In Pancreatic Cancer
Prof. J.J.C. Neefjes, Leiden University Medical Center, Dr N. Liv, UMC Utrecht
"Pancreatic adenocarcinoma (PDAC) has an extremely poor prognosis, and there is an urgent need for original therapeutic perspectives. Pancreatic cancer cells heavily depend on rewiring of their digestive system, the endo-lysosomal pathway, to sustain metabolic advantages in their nutrient-poor environments. Targeting endo-lysosomal dependencies of PDAC cells thus provides an original perspective and has the potential to create ground-breaking treatment opportunities. Here, we combine our synergistic expertise in cancer cell biology, biochemistry, genome-editing, and advanced microscopy to:
- Identify novel endo-lysosomal proteins harnessed by PDAC cells to gain metabolic advantage
- Resolve the regulation of endo-lysosomal pathways by PDAC driver genes
- Develop therapeutic strategies to target endo-lysosomal function in PDAC
This curiosity-driven project will reveal unrecognized mechanisms regulating cancer cell metabolism in PDAC and open novel avenues for therapeutics."
Signal symbiosis: exploring the co-regulation of metabolism and transcription in embryonic cell fate
Prof. P.J. Coffer, UMC Utrecht, Dr M.S. Bauer, TU Delft, Dr K.F. Sonnen, Hubrecht Institute
How do metabolic processes and signaling pathways work together to control early development in mammalian embryos? Here we will address this by studying the formation of somites—structures that give rise to bones, muscles, and vertebrae. While we know that specific genes and signals guide this process, recent research shows that metabolism plays a crucial role too. By studying the interaction between metabolism and gene activity, this research seeks to explain how cells decide their fate and organize during development. Using cutting-edge techniques, such as single-cell imaging and biochemical tools, we will explore how metabolic enzymes and their byproducts impact gene regulation. The findings could improve our understanding of congenital disorders, tissue regeneration, and stem cell therapy, while also providing insights for bio-engineering. This innovative project combines biology, biochemistry, and computer modeling to explore a largely uncharted area of developmental biology.
The mitochondria connection in neurodevelopmental disorders
Prof. N.N.K. Nadif Kasri, Radboudumc, Dr M.J.W.A.H. Adjobo-Hermans, Radboudumc
Dr W.J.H.K. Koopman, Radboudumc, Prof. C.L. Lohmann, Netherlands Institute for Neuroscience
Prof. B.B.A. de Vries, Radboudumc
Neurodevelopmental disorders (NDD) affect approximately 120 million people globally, causing reduced lifespans and high disability rates, especially in young individuals. Current treatments for NDD provide only symptomatic relief, leaving a critical need for new approaches. We here will investigate if and how energy metabolism dysfunction plays a significant role in NDD development. We do this with the aim to uncover critical disease pathways and therapeutic possibilities, uniting experts in NDDs, neuronal circuitry, and mitochondrial biology.
The Tumour-Stroma SialogGlycan Checkpoint: unraveling Siglec-dependent immunosuppression
Prof. Y. van Kooyk, Amsterdam UMC, Prof. A. Cambi, Radboudumc
The tumor microenvironment of pancreatic cancer one of the most devastating types of cancer consists of a complex network of tumour, stromal, and immune cells that evolves over time, creating an environment that supports immune suppression, impairs therapy efficacy and favours tumor growth. Understanding these cellular and molecular interactions responsible for weakening the immune system is crucial for improving diagnostics and therapies. One key, yet underexplored, mechanism that leads to immune dysfunction is the addition of sialic acids (small sugar molecules) to proteins. We have discovered that some of these sugars on pancreatic tumour as well as on fibroblasts can bind to specific receptors, called Siglec receptors, on immune cells. This binding promotes unwanted immune suppression but the specific mechanisms remain unclear.
Our goal is to fill this knowledge gap and generate new knowledge to develop new anti-tumor strategies and improve therapeutic outcomes.
Roll of the DICE?: Dissecting Immune Checkpoint blockade toxicity from Efficacy
Prof. J.G.J.V. Aerts, Erasmus MC, Prof. R.A. de Boer, Erasmus MC, Dr F. Dammeijer, Erasmus MC
Dr F. van Maldegem, Amsterdam UMC, Dr W.G. Meijers, Erasmus MC
Immunotherapy is a relatively new form of therapy for patients with a variety of cancers but can result in development of severe autoimmune toxicity. Autoimmunity results from activation of immune cells by immunotherapy directed to healthy organs such as the heart which can be fatal. Why some patients develop beneficial anti-tumour immune responses to immunotherapy and others direct their response to self, remains unknown. In a collaboration between thoracic oncologists, cardiologists, immunologists and bio-informaticians across several institutes we aim to uncover how autoimmunity is induced in the presence of tumour. We will make use of state-of-the-art translational mouse models of immunotherapy toxicity, use patients samples from established databases and validate treatment targets to look for novel therapies ameliorating toxicity while preserving treatment efficacy. With this approach we strive for better safety of immunotherapy directly impacting cancer patient quality of life.
The impact of childhood sexual abuse on endometrial tissue in women with endometriosis (CHASE study)
Prof. J.J. van Os, UMC Utrecht, Dr N. van Hanegem, UMC Utrecht, Dr J. van 't Hooft, Amsterdam UMC, Dr A. Romano, Maastricht UMC+, Dr G.S. Steba, UMC Utrecht, Dr I. Bicanic, UMC Utrecht
Childhood sexual abuse and endometriosis are both associated with dysregulation of the stress system. Our hypothesis is that chronic stress associated with childhood sexual abuse can cause progression of endometriosis. We will study the impact of childhood sexual abuse on endometrial tissue through hormone dysregulation and modifications in genetic expression (epigenetic). We want to investigate this by creating a biobank of blood, hair, endometrium and endometriosis tissue of women with endometriosis. We will compare hormone dysregulation and epigenetic modifications between women who have and did not have experienced sexual abuse. We will also investigate how often sexual abuse occurs in endometriosis patients and work on optimization of screening process in clinical practice. This research will provide mechanistic insight on endometriosis, but could also lead to other, potentially more effective, treatment strategies.
Genomic profiling and subsequent ex situ treatment of injured human donor livers
Prof. E. Berezikov, University Medical Center Groningen, Prof. F. Kuipers, University Medical Center Groningen, Prof. V.E. de Meijer, University Medical Center Groningen, Prof. ir. J. de Ridder, UMC Utrecht, Dr B.J. Tops, Princess Máxima Center for Pediatric Oncology
Liver transplantation is the only life-saving treatment for patients with end-stage liver disease. Unfortunately, 15% of patients in need of a transplant currently die while waiting for a donor liver. At the same time, 40% of available donor livers are not used because they fail to meet strict quality criteria. We have shown that donor liver quality can be assessed by placing them on a pump, a process called normothermic machine perfusion (NMP). However, NMP is time-consuming, expensive, and it is difficult to predict in advance whether it will be effective for a particular donor liver. In this project, we aim to develop a genomics-based predictor using gene expression and DNA methylation data. This tool will help improve the selection of donor livers suitable for transplantation, avoiding unnecessary NMP procedures, ultimately increasing the number of transplantable livers, and reducing waitlist mortality.
Biology and AI synergy for personalized therapy and identification of autophagy-deficient cancers
Dr K.M.A. Rouschop, Maastricht University, Prof. A.L.A.J. Dekker, Maastricht UMC+, Dr I.V. Samarska, Maastricht UMC+
Autophagy is a waste recycling process that facilitates cancer cell survival under stress and is essential for cancer progression. Remarkably, our recent research has identified a group of autophagy-deficient cancers (ADC). These cancers represent a substantial subgroup with distinct clinical outcomes. Due to the absence of autophagy, these cancers rely on alternative pathways to manage cellular waste, making them vulnerable to targeted therapies.
ADCs result from the absence of one out of, at least, seven autophagy-related proteins, leading to a diverse group of tumors that are difficult to diagnose based on traditional techniques. Therefore, this project aims to use artificial intelligence (AI) and advanced imaging techniques to identify ADCs based on features present within clinical images (CT and/or MRI). In parallel, the biological mechanisms that facilitate ADC progression and compensatory mechanisms will be identified and explored for personalized therapeutic benefit.
Decoding the Individual Vaccination response in older adults through immuno-Epigenetics – DIVE
Prof. D. van Baarle, University Medical Center Groningen, Dr J. Van Beek, RIVM, Dr A.M. Buisman, RIVM, Prof. B.T. Heijmans, Leiden University Medical Center, Dr Y. van Sleen, University Medical Center Groningen, Dr E.W. van Zwet, Leiden University Medical Center
To protect older adults from infectious diseases is a key societal challenge. Vaccination is a highly effective means to prevent life-threatening infectious diseases, but protection of older adults is nevertheless suboptimal, due to a decrease in immunity with age. This decline is different between individuals, making certain older adults particularly vulnerable for disease. However, this variation in vaccine responsiveness is not well understood and largely unpredictable. In this project, we will develop tools based on the epigenetic make-up of an individual and detailed immune function parameters to identify at-risk-individuals as well as understand the processed underlying this risk. The results will contribute to the development of more effective and tailored vaccination strategies for older adults which will lower the burden of infectious diseases.
Single-cell membrane protein characterisation to uncover the landscape of anti-cancer immunity
Prof. A.C.O. Vertegaal, Leiden University Medical Center, Dr A. Alemany, Leiden University Medical Center, Prof. G. Dittmar, Luxembourg Institute of Health
For the treatment of cancer, it is important to understand the complex interplay between the tumour and its environment. Single-cell RNA sequencing played a pivotal role in untangling the complex signalling systems of the tumour environment. However, not all changes in the RNA topography are translating into proteins. Understanding the changes of especially the proteins on the cell’s outer membrane and how the ubiquitin-proteasome system reshapes this protein landscape is important for a better understanding of the underlying processes. With the latest breakthroughs in mass spectrometry, the proteome of single cells can be measured, filling this important gap. In this project we will focus on the function of the proteins of the outer membrane and their key role in immunity with single-cell resolution.
Characterization of autoreactive B cells in rheumatoid arthritis: the tissue is the issue!
Prof. S.W. Tas, Amsterdam UMC, Dr J. Suurmond, Leiden University Medical Center
This project focuses on rheumatoid arthritis (RA), a chronic inflammatory joint disease. In RA, certain white blood cells called B cells play a harmful role by promoting inflammation in tissues such as the joints, which can lead to pain, disability, and a lower quality of life. At present, it is not known how these harmful (autoreactive) B cells develop and persist, because these processes occur in organs that are difficult-to-reach. Our goal is to study autoreactive B cells from different parts of the immune system (i.e. blood, lymph nodes, bone marrow, and inflamed joint tissue) at various stages of RA. We will investigate how these cells change over time and how they can be stopped from causing damage. The results could help discover new treatments to prevent or better manage RA, improving patient health and reducing healthcare costs, and may serve as a blueprint for other autoimmune diseases.
Guts to beat depression!
Dr R. Kraaij, Erasmus MC, Prof. S. Brul, University of Amsterdam, Dr A. Lok, Amsterdam UMC
Dr R. Quax, University of Amsterdam
Depressive disorders cause significant disability, mortality and economic impact, with current treatments often inadequate. The gut microbiome - a diverse community of microbes in the digestive system - shows strong, replicable links to depression. This project aims to explore gut microbiota and their products as potential new interventions for depression.
The goal is to identify bacterial targets for diagnosing, treating, or preventing depression. This project will extend research to multi-cohort, longitudinal studies, examining temporal and causal relationships and considering ethnic and sex differences. It will also explore interactions between microbial groups and validate promising candidates in preclinical models.
The project aims to recommend prebiotics and probiotics for clinical testing, addressing the need for better depression treatments. Results will benefit both academic and industrial partners in food and pharmaceuticals.
Stem cell therapy during ex-situ machine perfusion to harness inflammation in liver transplantation
Dr J. de Jonge, Erasmus MC, Prof. ir. M. Ottens, TU Delft, Dr E. de Pater, Erasmus MC
Liver transplantation is the only cure for end-stage liver disease, but the availability of donor organs is declining, especially in Western countries. Aging populations and lifestyle-related fatty liver disease are expected to worsen this shortage. Using suboptimal donor livers could address this issue, but these organs are more prone to complications due to oxygen deprivation. Hematopoietic stem cells (HSC), which are mobilized from the bone marrow after liver damage, have anti-inflammatory effects and promote liver repair, though their exact mechanism remains unclear. Machine perfusion, where an organ is oxygenated outside the body, offers a way to repair suboptimal livers with HSC before transplantation. This project will explore how HSC contribute to liver regeneration and test their safety and optimal dosage during machine perfusion. New detection techniques will ensure the safe use of repaired donor livers, potentially increasing the number of usable organs for transplantation.
Respiratory muscles in end-stage lung disease: pathophysiological processes & clinical consequences
Dr M.L. Duiverman, University of Groningen / University Medical Center Groningen, Dr J. Doorduin, Radboudumc, Dr M. Hellemons, Erasmus MC,Prof. C.A.C. Ottenheijm, Amsterdam UMC, Dr S.D. Pouwels, University Medical Center Groningen
To breathe effectively, intact lungs, but also strong respiratory muscles are required. In 25% of patients with advanced lung disease, the respiratory muscle pump fails, resulting in chronic hypercapnic respiratory failure, which has detrimental effects on prognosis and symptom burden.
This project aims to unravel underlying mechanisms and clinical implications of respiratory muscle failure in severe COPD, in order to enhance patient selection for existing therapies, provide more personalized treatment strategies, and pave the path for innovative interventions that reinforce respiratory muscles. We hypothesize that respiratory muscle dysfunction is caused by atrophy and reduced contractility of muscle fibres, that respiratory muscle dysfunction is exacerbated by non-invasive ventilation and contributes to difficult recovery following lung transplantation. A unique expert collaborative team will investigate this by combining functional respiratory muscle testing with muscle biopsies.
Interrogating microplastics as an environmental driver of lung cancer origin
Prof. B.N. Melgert, University of Groningen, Dr S. Prekovic, UMC Utrecht
Researchers from the University of Groningen and UMC Utrecht are investigating whether and how microplastics can cause lung cancer. Microplastics are everywhere: in the air, water, and even in our bodies. This study examines if inhaling microplastics can change lung cells, turning them into cancer cells. The project has two main goals: first, to investigate how microplastics affect the behaviour and gene activity of lung cells, potentially leading to cancer; and second, to examine how these microplastics alter the surrounding lung tissue, making it easier for cancer to develop and spread. By combining their expertise in lung biology and cancer research, the team hopes to find new ways to prevent or treat cancer. This research is important because little is known about the health risks of environmental contaminants like microplastics. Therefore, the results from this study have the potential to influence policies on plastic use.
TherapE3: Novel (immuno)therapy approaches in colorectal cancer using targeted protein degradation
Prof. M.M. Maurice, UMC Utrecht, Prof. M. Vermeulen, Netherlands Cancer Institute, Dr D.S. Thommen, Netherlands Cancer Institute
Current precision medicine commonly blocks the function of specific proteins. Despite successes, many patients have remained unresponsive and, moreover, these treatments often generate severe side effects and toxicity. In this project, the researchers focus on a novel strategy to interfere with cancer cells in which target proteins at the cell surface are removed and destroyed by the cell itself. An important goal of this project is to obtain an in-depth understanding of how this strategy works and how this approach can be optimized for treatment of cancer cells while sparing healthy tissues.
'NEUROtrans': Effects of Hormonal Intervention on Brain Development in Transgender Youth
Prof. C.F. Beckmann, Radboudumc, Prof. H.L. Claahsen- van der Grinten, Radboudumc
Dr G. Collin, Radboudumc, Dr K.V. Haak, Tilburg University, Dr S. Burke, University Medical Center Groningen
Transgender and gender diverse youth (TGDY) experience a mismatch between their biological sex and gender identity. This can cause significant distress, known as gender dysphoria (GD). Individuals with gender dysphoria who entered puberty can receive therapy with sex hormones, first to suppress further pubertal development and later to support transitioning into their gender. Understanding how hormone therapy impacts brain and cognitive-emotional development would greatly enhance clinicians’ ability to counsel individual patients and to make evidence-based recommendations.
We will advance understanding of the influence of sex hormones on brain and cognitive development through a precision medicine approach. We will create an internationally unique neuroimaging-based data resource that in turn will facilitate investigations into the specific impact of sex hormones on the development of critical brain regions and associated cognitive and behavioural functions.
Phase separation-controlled gene transcription in leukemia
Prof. J.J. Schuringa, University Medical Center Groningen, Prof. P.R. Onck, University of Groningen
Acute myeloid leukemia (AML) is a blood cancer that remains extremely difficult to treat. AML is caused by aberrations in the DNA, which disturb the normal differentiation process from hematopoietic stem cells to mature functional blood cells. As a consequence, gene expression control is altered. Based on research over the past years, it has become clear that gene expression control is not only a biological process, but also a physical process. Many transcriptional regulators have unique physical properties, they are often intrinsically disordered, meaning that these proteins do not have a rigid predefined structure. Rather, they have the capacity to interact with various other proteins, thereby forming so-called transcriptional condensates, which are gel-like structures on the DNA. The main aim of the current proposal is to dissect the composition and function of these condensates in detail, with the ultimate aim of identifying novel ways to treat AML patients.
Predictions of T cell receptor-antigen interactions through new high-throughput approaches
Prof. C. Joo, Delft University of Technology, Dr R.G.H. Lindeboom, Netherlands Cancer Institute
This research aims to improve our understanding of how immune cells distinguish healthy from cancerous or infected cells. The immune cells can sense these harmful cells by recognizing specific molecules presented on their surface. However, predicting which immune cells will react to which threats is difficult because of the vast number of presented molecules. This project will develop new biotechnology tools to quantitatively study these interactions, allowing scientists to measure the interaction strengths and possibilities of many immune cells and threats at once. The research will use computer models to predict these reactions, which could lead to new treatments for diseases like cancer and autoimmune conditions.
Targeting lipid metabolism to develop host-directed therapeutics for mycobacterial infections
Prof. P. Spaink, Leiden University, Dr M.E. Kavanagh, Leiden University, Dr A. Saris, Leiden University Medical Center, Dr W. Hoefsloot, Radboudumc
Infections caused by mycobacteria kill more than 1.3 million people annually. Existing treatment requires taking multiple drugs over a 4-48 month period, which results in significant toxic side effects, social, and economic costs. Furthermore, these treatments are rapidly becoming ineffective due to antibiotic resistance. MycoLipid will address this global challenge by developing novel host-directed therapies (HDTs), that are less susceptible to antibiotic resistance and can improve the safety and efficacy of existing drugs. These HDTs will boost the antibacterial response of immune cells and deprive infecting bacteria of nutrients by targeting host-lipid metabolism. MycoLipid’s team of experienced scientists and clinicians will use an innovative combination of state-of-the-art technologies to identify new drug targets and drug candidates, and validate these using patient-derived samples, thus ensuring groundbreaking advances in science and translation to improved patient treatments.
Novel CAAR-T cell strategy to tackle complex autoantigen-driven autoimmune diseases
Prof. M.H.M. Heemskerk, Leiden University Medical Center, Dr K.M. Bonger, Leiden University
Dr M.G. Huijbers, Leiden University Medical Center, Prof. H.U. Scherer, Leiden University Medical Center, Dr J.M. Weber, Delft University of Technology
Most human autoimmune diseases (AIDs) are chronic conditions without a prospect of cure. The advent of Chimeric Antigen Receptor (CAR)-T cell therapies marks a groundbreaking advancement in cancer treatment. First results using CAR-T cells in B cell mediated AIDs now also show highly encouraging, potentially curative effects. However, such therapies indiscriminately target all B cells which leaves patients vulnerable to serious infections. In contrast, precise immunotherapies that specifically target pathogenic B cells while preserving healthy ones offer a promising avenue for
safely managing and curing AIDs. Chimeric Auto-Antigen Receptor-T cells (CAAR-T cells) provide a platform capable of antigen-specific B cell targeting. Here, we aim to develop a novel approach to selectively target pathogenic B cells to such autoantigens allowing their selective killing by redirected CAAR-T cells in AID patients.
PURE-NET-SCD: Unravelling the mechanisms of inherited Purkinje network-based sudden cardiac death
Dr C.A. Remme, Amsterdam UMC, Dr M. Bellin, Leiden University Medical Center, Dr E.M. Lodder, Amsterdam UMC, Dr P.G. Postema, Amsterdam UMC
Sudden cardiac death due to cardiac arrhythmias in young adults is usually caused by mutations in genes that regulate the function of the heart. In certain hereditary heart rhythm disorders, knowledge of underlying disease mechanisms is insufficient, limiting options for treatment. Patients with a mutation in the DPP6 gene show a high risk of sudden cardiac death due to arrhythmias that arise from the Purkinje network, a part of the heart which is important for proper electrical conduction. Currently, no adequate treatment is available for affected patients and sudden death may only be prevented by an implantable defibrillator, which is often accompanied by complications. This project will investigate the effect of the DPP6 mutation in the different cell types of the Purkinje network, using an animal model and patient-specific stem cells, with the aim of developing new strategies for risk stratification and therapy.
Per- and polyfluoroalkyl substances (PFAS) and their impact on vaccine responses in the Netherlands
Prof. L.G. Visser, Leiden University Medical Center, Dr M.C. Coppola, Leiden University Medical Center, Dr F.K. van der Klis, RIVM, Dr A.R. Roukens, Leiden University Medical Center, Dr I.V. van der Veen, VU University Amsterdam, Dr J.W. de Wit, RIVM
Per- and polyfluoroalkyl substances (PFAS) are a group of synthetic compounds utilized since the mid-20th century in products due to their useful characteristics. PFAS are often called "forever chemicals" because they do not break down via natural processes. Most people in the world are exposed to mixtures of PFAS, and the primary exposure route to PFAS in non-occupational settings is via the diet. Multiple studies show that the most critical health effects associated with PFAS exposure are: decreased vaccine responses, increased serum cholesterol and decreased fetal growth. Over the years, PFAS exposure has been subject of debate and has led to much interest from citizens, who are concerned about exposure to these chemicals, and whether they affect their health.
In this project, we will address several important knowledge gaps to understand the role of vaccine-induced immunity as most critical outcome of health impact of PFAS. Results of this research can contribute to future policy
SPAR-HF: SPAtial Regulation in Heart Failure
Dr L.W. van Laake, UMC Utrecht, Prof. L.H. Franke, University Medical Center Groningen
End-stage heart failure (ESHF) is a life-threatening condition that often requires radical treatments like heart transplantation. Variants in the DNA, so-called genetic factors, can make a person more likely to develop certain diseases or experience a fast progression of their disease. However, we still do not understand the genetic factors that cause ESHF. This makes it difficult to identify which patients or their family members are at risk and how best to treat them. In SPAR-HF, we will use cutting-edge technologies to study local gene activity in 60 human heart samples in great detail. We will then compare these results with previously obtained genetic data from blood samples of 43,000 persons and medical information of 12,500 ESHF patients. This innovative approach will allow us to discover new gene variants that underlie ESHF, so that we will better understand the disease and find new ways to improve diagnosis and treatment.
Boundaries to mutagenic repair of chromosomal breaks to prevent disease
Dr J.J.L. Jacobs, Netherlands Cancer Institute, Prof. M. Tijsterman, Leiden University Medical Center
Human health and development rely on the precise replication of DNA, repair of damaged DNA, and protection of telomeres (chromosome ends). Mistakes in these processes can lead to diseases, cancer, and aging. While substantial progress is made in understanding how cells maintain their genetic integrity, many questions remain unanswered. This project aims to uncover how cells manage DNA synthesis during the repair of broken chromosomes, particularly focusing on a type of mutation called tandem duplications (TDs). TDs are common in animals and plants genomes, and are increased in certain cancers, but their origins are unclear. Preliminary research suggests that errors in DNA packaging soon after DNA replication can lead to TDs and increase cancer risks. The project also explores the link between TDs and a cancer survival mechanism known as alternative lengthening of telomeres (ALT), hoping to provide new insights into these disease-causing processes.
