ZonMw Open Competition congratulates 31 research teams on the granted subsidy

HMGA1 Epigenetic Activation for Regeneration Through Chromatin Opening and Dedifferentiation
Prof. J.P.W.M. Bakkers, Hubrecht Institute Dr F. Mattiroli, Hubrecht Institute
Heart failure is a leading cause of death and disability worldwide, often resulting from damage caused by a heart attack. Unlike humans, some animals, such as zebrafish, can naturally regenerate their hearts after injury. This project aims to understand the fundamental biological mechanisms that enable such regeneration, focusing on a protein called HMGA1, which plays a key role in controlling how DNA is packaged and which genes are turned on or off. We have discovered that HMGA1 is active in regenerating hearts and helps heart muscle cells re-enter the cell cycle and replace damaged tissue—but only in specific regions near the injury. Using advanced techniques in genetics, single-cell analysis, and spatial transcriptomics, we will explore how HMGA1 interacts with the local environment and modifies chromatin to trigger regeneration. By studying these processes in zebrafish, mice, and human heart cells, we aim to uncover conserved biological principles that explain why regeneration is possible in some species but not others, providing new insights into heart development and repair.

Fact or fiction: Type II nuclear receptors are obligate heterodimer partners of RXR
Prof. S.W.C. Mil, UMC Utrecht, Dr C.D. Okafor, Pennsylvania State University
Our livers use nuclear receptors (NRs) to control how we store and use fats and sugars. Three important NRs — FXRα, LXRα and PPARα — were thought to always work by pairing with another protein called RXR. Drugs that target these receptors could potentially treat common metabolic diseases (like diabetes or high cholesterol), but current drugs often cause unwanted side effects.
We found something surprising: FXRα can also pair with itself and bind to different spots on DNA, turning on different genes than the usual RXR partnership. We show that the self-paired shape is very different from the RXR partner shape. This means these receptors are more flexible and complex than previously anticipated.
We will study how common these alternative pairings are, how they change liver function, and whether we can steer pairing to create safer, more effective drugs. This could lead to better treatments for metabolic disease with fewer side effects.

Mechanical Memory in Metastasis Formation (MEMO)
Prof. O. Kranenburg, UMC Utrecht, Dr M. Gloerich, UMC Utrecht, Dr J. Hagendoorn, UMC Utrecht, Prof.G. Koenderink, TU Delft
Cancer is the most common cause of death in the Western world. Patients usually die because of the formation of distant metastases. Research on metastatic behavior focuses primarily on genetics, cell biology, and immunology. Tumor cells also experience mechanical forces, both in primary tumors and during metastasis to other organs. They respond to these forces by activating survival programs, resulting in more aggressive behavior. Temporary forces can even cause long-term changes in behavior. This phenomenon is called "mechanical memory." Our work demonstrates that the mechanical memory of colorectal cancer cells is activated during metastasis to the lungs. In MEMO, we will investigate exactly how this mechanical memory is activated and how it contributes to the formation of metastases. A better understanding of the biophysical aspects of metastatic behavior can help develop strategies for prevention, diagnosis, and treatment.

Chemotherapy-Induced Neurotoxicity and Transcription Stress: Mechanisms and Therapeutic Strategies
Prof. J.A.F. Marteijn, Erasmus Medisch Centrum, Dr D.L.C. Berg, Erasmus Medisch Centrum, Prof. S.B. Schagen, Netherlands Cancer Institute
Chemotherapy improves cancer survival, but many patients experience long-term changes in cognitive function, often called “chemobrain.” This includes problems with memory, concentration, and information processing, affecting the quality of life in about half of all chemotherapy-treated patients, sometimes even decades after treatment. Currently, there are no proven ways to prevent or treat these issues. Our project aims to understand why chemotherapy affects neurons, long-lived brain cells essential for memory and thinking. Unlike dividing cells, neurons have limited DNA repair capacity and depend on accurate gene transcription. Chemotherapy-induced DNA damage can block this process, leading to impaired neuronal function and cognitive decline. By combining the expertise of the Marteijn, Van den Berg, and Schagen labs, we investigate how chemotherapy interferes with transcription, how DNA repair protects neurons, and how failure of these processes contributes to cognitive problems. These insights may guide the development of new strategies to prevent or reduce “chemobrain.”

Neurodevelopmental deficits in IEI - brain and immune system mechanisms (IMBRAIN)
Dr V.A.S.H. Dalm, Erasmus Medisch Centrum, Dr I. Da Silva Serra, Erasmus Medisch Centrum, Prof. S.O. Dumoulin, Spinoza Centre for Neuroimaging, Dr M.J.G. Kooiker, Erasmus Medisch Centrum, Dr T. van den Broek, UMC Utrecht
People with complex inborn errors of immunity (IEI) typically suffer from infections, auto-immune disease and malignancies. However, these disorders may also present with other, less well understood symptoms, like neurological deficits and psychological symptoms.
In this project our team will focus on a rare IEI, called APDS, which is caused by a gene mutation and affects both the immune system and the brain. The goal is to understand how brain and behavior problems develop in APDS and whether they can be treated. Researchers will use mouse models, brain scans, blood tests, and a mobile app to study learning, behavior, and brain structure. We will also test how a drug called leniolisib affects both the immune system and brain function. This is the first study to combine multiple medical fields to better understand and treat whole-body symptoms in patients with IEI.

Protein noise in early development and its potential role in developmental disorders
Prof. B. Burgering, UMC Utrecht, Dr M.K.K. Hansen, Radboud University
All complex organisms, including humans, start from a small group of identical cells that gradually develop into many different cell types. This process requires cells to make very precise fate decisions. If these decisions go wrong, it can lead to serious developmental disorders. Traditionally, such disorders are explained by genetic mutations, but new research suggests that non-genetic factors, such as random fluctuations in gene activity—known as gene expression noise—could also play an important role. In this project, we will study how cells regulate noise to ensure accurate development. Using cutting-edge single-cell technologies, we will measure noise at the protein level, which has never been possible before, and identify factors that control it. By uncovering how noise is controlled, we aim to reveal new mechanisms that shape healthy and diseased development.

The transgenerational impact of Socio Economic Status on Mental Health; Inheritance revisited
Dr M.P.M. Boks Amsterdam UMC, Dr C.A. Cecil Erasmus Medisch Centrum, Prof. J.O. Mierau University of Groningen, Prof. B.W.J.H. Penninx Amsterdam UMC, Prof. K.J.H. Verweij Amsterdam UMC
Mental disorders are often considered hereditary, yet genes are only part of the story. Socioeconomic circumstances such as poverty and work also play a major role. Their impact can carry over from parent to child, creating the appearance of inheritance and sustaining inequalities in health. This project investigates three pathways. First, dynastic effects: parental problems, including mental disorders, may cause financial insecurity or stress at home, raising children’s risk. Second, gene–environment correlations: genetic vulnerabilities may coincide with greater likelihood of experiencing
socioeconomic disadvantage, making genes and environment difficult to separate. Third, epigenetic changes: experiences of poverty or stress may leave biological marks, such as DNA methylation, which can be passed from parent to child. Using data from large Dutch cohort studies, we examine how these processes jointly shape mental health across generations. Findings will guide policy
and prevention efforts to break the cycle of poverty and mental disorders.
 
GLYCELL: Glycan-mediated cell crosstalk in metabolic dysfunction-associated steatotic liver disease
Dr B.G.A. Guigas Leids Universitair Medisch Centrum, Dr N. Haan Leids Universitair Medisch Centrum, Dr A.G. Holleboom Amsterdam UMC
Steatotic liver disease affects more than 30% of the world’s population, especially patients with obesity and type 2 diabetes. This disease starts with accumulation of fat, and often progresses into a more severe form, with inflammation and fibrosis. Alterations in the communication between the different liver cell types is central in disease progression, but remains incompletely understood. In our GLYCELL project, we will investigate the role of specific complex sugar structures (glycans) in the development of the aggressive liver disease. These glycans are decorating all cells in the human body and modulate cell communication. We will develop and use innovative mass spectrometry approaches to map liver glycans in cohorts of patients with steatotic liver disease. Next we will modify the glycans in advanced human model systems to investigate their function in the disease process. This fundamental project will provide new molecular insights and contribute to the development of targeted therapies.

Translational strategies for lymphatic anomalies in RASopathies
Prof. S.N. Wildt Radboudumc, Dr A.H. Greupink Radboudumc, Prof. J. Hertog, Hubrecht Institute, Dr E.K.S.M. Leenders, Radboudumc
RASopathies are hereditary disorders in which an error in the cell leads to disruptions in the growth and development of organs. Some patients therefore develop severe problems with their lymphatic vessels. These problems can sometimes be life-threatening, and existing treatments do not always work. Because the disease is so rare, good treatment options are lacking.
This project investigates how lymphatic vessels develop abnormally in RASopathies and seeks sustainable treatment options. To do this, we use zebrafish, patient blood samples, and computer models. The research also examines whether existing medicines might still be effective and suitable for children, adults, and even for use during pregnancy.
This study not only provides greater insight into the formation of lymphatic vessels but also leads to new treatment options. This can help prevent severe symptoms, prolonged hospitalizations, and invasive surgeries, thereby significantly improving the quality of life for patients and their families.

Unraveling the neuroplastic effects of Electroconvulsive Therapy (ECT) in Depression
Dr A. Dols, UMC Utrecht Brain Center, Dr E. Dellen UMC Utrecht, Dr. P. Van Eijndhoven Radboudumc, Dr L. Douw Amsterdam UMC, Prof. I. Huitinga, Netherlands Institute for Neuroscience, Dr K.W.F. Scheepstra Amsterdam UMC
Our brains are not fixed: they can adapt, for instance by forming new connections between nerve cells. This ability, called neuroplasticity, is important for recovery from several psychiatric illnesses, such as depression. Electroconvulsive therapy (ECT) is currently the most powerful treatment known to boost neuroplasticity. During ECT, a brief electrical pulse triggers a controlled seizure in the brain. Yet we still do not fully understand the changes ECT produces in the brain. Uncovering this is key to improving treatments for mental disorders. We think that ECT restores a balance in excitability in the brain that is important for the adaptive capacity. This project will study ECT’s effects on the brain at multiple levels. We will use brain scans in patients receiving ECT to measure changes in brain structure, function, and connections. Additionally, we will study donated brain tissue from people who received ECT to look at changes in cells. By combining these approaches, we aim to find biological markers that explain ECT’s effects and can advance psychiatric treatment strategies

REFINE - Reducing unnecessary appendectomies: Focus on the patient and environmental impact
Prof.  N.D. Bouvy Maastricht University, Dr J. Jansen Maastricht University, Dr R.M.J.J. Kleij Leids Universitair Medisch Centrum, Prof. H.F. Lingsma Erasmus Universiteit, Dr  J.S.D. Mieog Leids Universitair Medisch Centrum, 
Dr H. Ismaïli M'hamdi Maastricht University
Every year, thousands of people in the Netherlands undergo surgery to remove their appendix. In many cases this is needed, but sometimes the infection can also be treated safely with antibiotics. Research shows both treatments are equally safe, yet surgery is still chosen more often. This leads to unnecessary operations, higher costs, extra pressure on staff, and more impact on the environment.
The REFINE project studies how to organize this care in a smarter and more sustainable way. We look at recovery time, complications, staff use, costs, and environmental effects, alongside medical results. We also examine behavioral factors - such as knowledge, attitudes, and preferences - and ethical questions.
Together with patients, clinicians like GPs, and surgeons, we aim to provide the right treatment, in the right place, with benefits for patients, healthcare, and the planet.

Maintain Muscle and Brain: Dissecting Disrupted Neuromuscular Communication in Myotonic Dystrophy
Prof. J.H.L.M. Bokhoven Radboudumc, Prof. R.J. Pasterkamp UMC Utrecht, Dr D.G. Wansink Radboudumc
Myotonic dystrophy type 1 (DM1) is a genetic muscle disease and the most common form of muscular dystrophy in adults. It affects not only muscles but also the nervous system, especially in severe cases present at birth. DM1 is caused by a genetic mutation that disrupts how cells process RNA, leading to muscle weakness and other symptoms. Studies have shown that DM1 also affects the connection between nerves and muscles (neuromuscular junction), which may explain some of the disease’s effects.
Current research models don’t fully capture how DM1 works, especially at the nerve-muscle interface. This project aims to develop advanced lab-grown models using human stem cells to better study these processes. These models could help us to understand DM1 more deeply and explore new treatment options—without using animals.

Collaborative Intelligence: Clinician-AI Partnerships for Cancer Treatment Planning and Monitoring
Prof. S. Ben Allouch Amsterdam University of Applied Sciences, Dr K.B.W. Groot Lipman, Netherlands Cancer Institute, Dr D.M.J. Lambregt Netherlands Cancer Institute, Dr. B.Y. Yu Amsterdam University of Applied Sciences 
Artificial Intelligence (AI) is changing the way we look at cancer scans. In research, AI has already shown that it can spot cancers, outline tumors, and track treatment response faster and often more accurately than doctors. But while the technology is moving fast, its use in daily hospital practice is still limited — both in the Netherlands and worldwide. This gap is becoming more urgent as radiologists face heavy workloads, staff shortages, and the risk of burnout. In cancer care, many of the imaging tasks doctors perform — like measuring tumors to see if treatment is working, or carefully outlining a tumor before radiation therapy — are essential but also very repetitive and mentally draining. AI could help by taking over much of this routine work, giving doctors more time and energy to focus on what really matters: making complex decisions and working with other specialists to plan the best treatment. The challenge is that bringing AI into real-world cancer care isn’t just about building smart tools. It also requires making sure those tools fit smoothly into hospital workflows and truly support the doctors who use them.
 
Foot4Thought: Multimodal modelling to understand and prevent foot deformities in cerebral palsy
Dr M.M. van der Krogt Amsterdam UMC, Prof.  A.I. Buizer Amsterdam UMC, Dr A. Seth TU Delft, Dr N. Tümer, TU Delft
During growth, children can develop an abnormal position of the feet. This may cause pain and difficulties with standing and walking. Such deformities often occur in children with brain injury, such as cerebral palsy (CP). How and why this happens, and which treatment is best, is still not well understood. Researchers at Amsterdam UMC and TU Delft will collaborate to better understand this. With CT-scans, they will measure the exact shape and orientation of the foot bones while standing. They will also assess the movements of the feet while walking using gait analysis. For each child, a personalized computer model will then be created. This will allowing precise calculation of the forces on the bones and their impact on bone growth. The researchers will also investigate whether and how different treatments can influence this growth. This knowledge will ultimately lead to prevention or improved treatment of foot deformities.

Glucopilot: Personalized glucose advice: a co-pilot at your side!
Dr M.R. Soeters Amsterdam UMC, Dr S. O'Donovan Eindhoven University of Technology, Prof. N.A.W. Riel Eindhoven University of Technology, Dr S.E. Siegelaar Amsterdam UMC
Diabetes is one of the fastest growing health problems worldwide, affecting more than half a billion people. Many more live with prediabetes, a condition that often progresses to diabetes and increases the risk of heart and vascular disease. Preventing diabetes through lifestyle is possible, but current advice is too general and does not account for individual differences. The GLUCOPILOT project aims to change this by developing a “co-pilot” that gives personalized guidance based on continuous glucose measurements. In our study, we will use a new non-invasive smart ring together with standard glucose sensors and other wearables to monitor glucose, sleep, activity, and stress. With advanced computer models, we will learn how these factors interact in each individual. The results will be translated into personalized lifestyle advice via a digital health app. GLUCOPILOT combines medical, technological, and societal innovation to improve prevention and health.

The power of modulating emotional memory in mental health treatment
Prof. M. Kindt University of Amsterdam, Prof. I.M. Engelhard Utrecht University, Dr D. Horstkötter Maastricht University, Prof. H.P. Otgaar Maastricht University, Prof. M.M. Rijkeboer Maastricht University
Despite advances in mental health care, diagnosis-specific approaches often fall short for complex conditions, prompting the development of therapies that address common underlying processes across disorders. One of these new and promising approaches, Imagery Rescripting, focuses on reshaping emotional memories to improve mental health. A major advantage of this approach is that it has the potential to provide a sustainable solution to challenges in mental health care. However, questions remain about how it works? Does it simply change the emotional significance of memories, or does it fundamentally alter the memories themselves? If the latter is true, what legal and ethical considerations arise when tinkering with someone's autobiographical memory? To explore these critical issues, experts from psychology, clinical practice, law, and ethics are collaborating to better understand the mechanisms behind Imagery Rescripting and its broader implications for clinical practice, society and individual rights.

From patients to mice: effects of poor sleep on the processing of fearful memories
Dr R.H. Havekes University of Groningen, Prof. H.W.H.G. Kessels University of Amsterdam, Dr S.L. Lesuis University of Amsterdam, Prof. E. Someren, Netherlands Institute for Neuroscience
Sleep is vital for memory. Poor sleep often results in disturbed memories and emotions, which contributes to stress and anxiety. Despite its importance in mental health, there is limited understanding of the mechanisms through which insufficient or poor sleep impacts emotional well-being, particularly how it exacerbates distressful memories. This research aims to investigate the brain mechanisms of how poor sleep worsens fear memories and explore potential interventions. Using brain activity recordings from more than 500 patients with insomnia, we identify patterns that reflect disrupted sleep. We then investigate these patterns in mouse models to study the underlying biological processes in detail. Finally, we test treatment strategies that target these mechanisms. The ultimate goal is to provide new entry points for therapies that improve sleep quality and reduce the risk of storing emotional or traumatic memories, thereby improving daily functioning and mental health in insomnia patients.

Unravelling causes and consequences of DNA replication stress during the first embryonic cell cycle
Dr B. Westendorp, Utrecht University, Dr M. Ruijter-Villani Utrecht University, Dr M. Zamani Esteki Maastricht UMC
In vitro fertilization (IVF) offers hope to couples with fertility problems, but succeeds in only 30% of cases due to aneuploidy—abnormal chromosome distribution during early cell divisions. Aneuploidy is the primary cause of failed implantation, miscarriage, and developmental defects. Its causes remain
unclear, but recent research suggests that DNA replication stress—impaired chromosome copying—may play a key role. Such stress, common in cancer cells, is also unusually high at the first cell division after fertilization. This project uses advanced microscopy and molecular genome analysis to uncover the molecular mechanisms of embryonic replication stress and to test how frequently it leads to aneuploidy in human embryos. The team will also investigate whether reducing replication stress in a veterinary IVF model can prevent aneuploidy. This may offer leads for improved IVF treatments.

Keeping track of antigenic drift, a booster for influenza A virus surveillance and vaccine selection
Prof. J. Huskens, University of Twente, Dr R.P. Vries Utrecht University
Why do people still die from flu worldwide and why do vaccines not function equally well every year? Flu viruses mutate fast, and thereby they change their properties. This way they escape from our immune system, which just got accustomed to an earlier variant (antigenic drift). Moreover, new viruses learn to jump from wild bird populations to people (zoonosis). Mutations affect foremost the two most important viral coat proteins: hemagglutinin (HA) and neuraminidase (NA). Particularly crucial are the interactions these proteins make with glycans at cells in our respiratory tract. How HA and NA act together is still largely unknown. This project explores the binding and reaction patterns of these proteins with dedicatedly designed glycan surfaces. The results will contribute to better insight into antigenic drift and the risk of zoonoses and can lead to new applications for improved surveillance and possibly even the prediction of future virus threats.

REPAIR: REscue of mitochondrial mutations in PAtient-specific Innovative Renal organoids
Prof. M.C. Verhaar UMC Utrecht, Dr J.H.F. Baaij Radboudumc, Dr M.A.J. Koppens UMC Utrecht
The REPAIR project tackles the urgent need to understand how mitochondrial DNA (mtDNA) mutations contribute to kidney tubulopathies, rare diseases affecting the kidney for which no curative treatment is available. Mitochondria are the cell’s powerhouses, especially important in energy-demanding kidney tubules. Recent evidence shows that mtDNA mutations play a larger role in these diseases than previously thought, but research has been limited by the lack of accurate lab models and tools to edit mtDNA. Our interdisciplinary team combines expertise in mitochondrial gene editing, kidney tubuloid models, and functional testing to uncover how these mutations cause disease. We will create patient-derived kidney models, correct mtDNA mutations using advanced techniques, and study the effects on ion transport. This work will reveal disease mechanisms, improve diagnosis, and guide the development of future treatments for patients across Europe.

When 1 plus 1 is more than 2 – molecular dissection of synergistic receptors on CD8 T cells
Prof. R. Arens Leids Universitair Medisch Centrum, Dr K. Ganzinger, AMOLF
Cancer immunotherapy uses the body’s own immune system to fight tumors by activating T cells, but current treatments only work well for some patients. One reason for this limitation is that T cells rely on multiple stimulatory “switches,” called costimulatory receptors, to fully activate and persist. How these receptors work together is poorly understood, limiting our ability to design more effective therapies.
This project aims to uncover how different costimulatory receptors cooperate to boost T-cell function. Using advanced imaging, molecular profiling, and engineered T cells, we will study these interactions in detail. We will then apply this knowledge to improve adoptive T-cell therapies, including CAR T cells and patient-derived tumor T cells, testing whether combining certain signals can make them more effective against cancer.
By linking fundamental discoveries to practical applications, this research may help design next-generation immunotherapies that work for more patients, increasing survival and quality of life.

Multi-disease tEsting: fRom Information to impacT (MERIT)
Prof. H. Koffijberg University of Twente, Dr D.M. Pegtel Amsterdam UMC, Prof. M.M.G. Leeflang Amsterdam UMC, Dr M. Huisman, Radboudumc
Within diagnostics, many so-called "multi-disease tests" are rapidly emerging. With only one blood prick or X-ray image, these tests measure the presence or absence of many diseases at once. They may find diseases before they cause problems. But by looking at many diseases they also have a much larger chance of indicating a disease is present even though that disease is not present in reality (called false positive outcomes). 
For single disease tests, researchers know how to balance the benefits of early diagnosis against the potential harm of false positive outcomes. Multi-disease tests are much more complex and standard single-disease analyses will not provide all the information users need. The researchers in this project will extend existing evaluation methods for single disease tests to multi-disease tests. These methods will support policymakers and physicians in making informed decisions about whether to purchase and how to use these novel tests.

Studying the functional impact of paracrine mediators of cardiac remodeling and repair
Prof. E. Van Rooij, Hubrecht Institute, Prof. R. Passier University of Twente
Heart disease is the world’s number one killer, claiming more than 17 million lives every year. A major reason is that the human heart cannot repair itself after injury. When heart muscle cells die, they are replaced by stiff scar tissue that weakens the heart and often leads to heart failure.
Remarkably, spiny mice (Acomys) are able to repair their hearts after damage without forming harmful scars. Instead, they create a flexible tissue environment that supports recovery. Our research has shown that fibroblasts – support cells in the heart – from Acomys send protective signals to heart muscle cells, while fibroblasts from ordinary mice (Mus) send damaging signals.
In this project, we will uncover the key signals that make the difference between harmful scarring and healthy repair. Using advanced human heart models grown from stem cells, we aim to translate these insights into new therapies to protect patients from heart failure.

Defining & targeting dysregulated atypical B cells in cardiovascular disease and multiple sclerosis
Prof. M.C. van Zelm Erasmus Medisch Centrum, Dr A.C. Foks Leiden University, Dr M.M. Van Luijn, Erasmus Medisch Centrum
Cardiovascular disease (CVD) is the leading cause of morbidity and mortality worldwide, and is a major contributor to morbidity in chronic immune disorders, especially in multiple sclerosis (MS). Aging is a key determinant for progression of both diseases, but its effects are impossible to predict or halt. Recent work by our team has revealed that a particular immune cell, atypical B cell (ABC), is involved in CVD and MS. However, ABC are also needed for protective immune responses. 
This project aims to define the role of ABC in disease progression and commonalities between people with CVD and MS. In addition, we aim to identify how to target these cells with therapeutics. We will examine well-defined CVD and MS patients, and test therapies in pre-clinical models.
Through combining the expertise of three research teams, we strive to provide new insights to optimize treatment and prevent disease progression of CVD and MS.

Eavesdropping on cryptic cytokine communication in T cells
Dr  J.B. Beltman Leiden University, Dr. M.C. Wolkers, Amsterdam UMC
Our immune system excels at clearing cancer cells, and of cells infected with viruses. T-cells have a key role in this clearance. To achieve this, T-cells produce signalling molecules like cytokines. The production of cytokines, their interplay and their effects on immune responses are tightly interlinked. This makes it difficult to intuitively understand the regulation of cytokine responses, which has consequences for generating effective therapeutic T-cells. In this project we will generate detailed experimental data using human T-cells and tumor cells to characterise cytokine responses. We will take measurements at different levels of regulation, and in different circumstances, such as in scenarios with molecular stress similar to that in tumors. We will use computer simulations that mimic and help explain these T cell responses and their effects on tumor targets. Ultimately, the gained knowledge should help to better design future immunotherapies.

Entering the Patient in the Drug Delivery Equation (Deliver-E)
Prof. L.B. Creemers Maastricht University, Prof. S. Abeln Utrecht University, Dr C.F. van Nostrum Utrecht University, Dr A.J. Feelders Utrecht University
Local injection of drugs loaded into biodegradable microspheres is a promising strategy; diseased tissues are exposed to an effective dose over a prolonged period, while minimizing exposure elsewhere in the body. However, only a few sustained-release formulations are currently available. There is a large gap between drug release dynamics in the human body and as typically measured, in a simple buffer solution. The Deliver-E project addresses this challenge by mimicking human physiological conditions in laboratory experiments, in constant interaction with machine learning modelling, translating the data into predictive models, while steering new experiments to generate new data to optimize the models. Ultimately, these models can serve as blueprints for the development of personalized drug formulations—initially for specific patient groups, and eventually even for individual patients. Deliver-E focuses on the nervous system for chronic pain and brain diseases but the models will be adaptable for use elsewhere in the body.

The hidden therapeutic relevance of the "dark genome" in colorectal cancer
Dr N. Leveille Amsterdam UMC, Dr S.A.A.C. Van Heesch, Prinses Máxima Center
Advanced colorectal cancer remains difficult to manage, with poor survival rates due to the lack of durable and effective therapies. To address this clinical challenge, our project explores the ‘dark genome’, a largely unexplored network of non-coding RNAs and microproteins increasingly recognized as pivotal in cancer biology. We will use cutting-edge sequencing to systematically identify long non-coding RNAs and microproteins expressed in CRC, followed by CRISPR/Cas-based functional genetic screens to evaluate their roles and impact on tumor growth and survival. This interdisciplinary effort combines Dr. Leveille’s expertise in lncRNA biology with Dr. Van Heesch’s knowledge of microprotein function. Together, this collaboration aims to uncover novel molecular vulnerabilities and lay the groundwork for innovative therapies that could significantly improve outcomes for patients with advanced CRC.

Cellular basis of clinical heterogeneity in SETD1A and SETD1B neurodevelopmental disorders
Dr O. Başak UMC Utrecht, Dr  N. Antón-Bolaños UMC Utrecht, Dr T.S. Barakat Erasmus Medisch Centrum
Neurodevelopmental disorders (NDDs) affect up to 15% of children and young people worldwide. These conditions often show similar symptoms, such as autism-like social deficits and seizures, but individuals with the same diagnosis can still be very different from each other. This makes it difficult to understand the causes and to find effective treatments. Recent research has shown that changes in how DNA is packaged and regulated — a process called "chromatin modification" — play a major role in NDDs. Our project focuses on two genes, SETD1A and SETD1B, which affect a specific chromatin marker and are linked to a wide range of symptoms. By using patient-derived stem cells to grow human brain cells in the lab, we aim to uncover how changes in these genes lead to different symptoms. This will help us better understand these disorders and develop more personalized, effective treatments in the future.

ENDO-SAB: unravelling immune endotypes in Staphylococcus aureus bacteremia
Prof. R. van Crevel Radboudumc, Dr A.N. Spaan UMC Utrecht
A bloodstream infection with the bacterium Staphylococcus aureus (SAB) is a potentially serious condition. The outcome can range from mild to life-threatening, such as sepsis. It is unclear why one patient gets severely ill but another does not. The ENDO-SAB project investigates if differences in the patients’ immune responses (“immune profiles”) can explain this. These profiles have proven important in other infections, but they have never been studied in SAB. In this project, existing and new patient groups will be examined using modern techniques that map patients’ proteins and genetic material. In this way, we aim to determine which immune profiles exist in SAB, how they relate to clinical symptoms and disease severity, and what role genetic and autoimmune factors play in these profiles. This knowledge may lead to better diagnostics, earlier recognition of high-risk patients, and the development of tailored treatments, such as targeted immune therapy.

Biomarker profiles in blood for the prediction of delayed ischemia in brain hemorrhages
Prof. D. Verbaan Amsterdam UMC, Dr M.G. Best Amsterdam UMC, Prof. N.P. Juffermans Erasmus Medisch Centrum, Prof. M.C. Schut Amsterdam UMC, Prof. C.E. Teunissen Amsterdam UMC
Aneurysmal subarachnoid hemorrhage (aSAH) is a severe type of brain hemorrhage with high morbidity. A feared complication is delayed cerebral ischemia (DCI), which is marked by focal brain ischemia within two weeks after the aSAH. DCI occurs in approximately 25% of the aSAH patients but till date predicting who will or will not develop DCI is challenging. Therefore, these patients remain admitted to the hospital wards for two weeks, postponing their rehabilitation process, and possibly reducing clinical outcome and quality of life. 
The aim of this project is to develop a blood test that measures several aspects in the blood including genetic markers and proteins, and clothing tendency. This data will be analyzed by artificial intelligence (AI) algorithms that will highlight the patients at highest risk of developing DCI. The performance of this AI-guided blood test will be tested in blood of aSAH patients admitted to other hospital. If successful, we aim to introduce this test into clinical practice.

The vicious circle of protein modification-induced chronic inflammation
Prof. L.A. Trouw Leids Universitair Medisch Centrum, Dr M.M.J. Van Greevenbroek Maastricht University
Health problem: The prevalence of cardiometabolic diseases and several autoimmune diseases is rising. The parallel increase suggests a common cause. Identification of the biological mechanism underlying such shared etiology would provide an opportunity to treat the root cause of these common diseases.
Hypothesis: Lifestyle, ageing and environmental triggers may modify proteins. Such post-translationally modified proteins (PTMs) trigger inflammation directly and also create an environment for formation of anti-PTM antibodies as the PTM proteins may be considered as “foreign” by the immune system. Presence of anti-PTM antibodies will further amplify the inflammatory response, exacerbating chronic low-level inflammation culminating into cardiometabolic and autoimmune disease. 
Originality:We will collaborate in a unique new team-based effort combining epidemiological studies using large human data sets obtained at the University of Maastricht with wet-lab experiments and in-vivo interventions at Leiden University. The project provides insights into PTM-driven chronic low-level inflammation and showcases the possibilities to intervene.