Off Road grant for 24 innovative ideas

Do you want to know more about the 24 approved projects? Click on the cross!

• Public summaries programme Off Road 2026

  Mechanisms of microglial endolysosomal exocytosis in Alzheimer’s disease
  Dr M.P. Bebelman, Utrecht University
  In Alzheimer’s disease, misfolded proteins form aggregates that build up in the brain and disrupt the function of nerve cells. The brain’s immune cells, called microglia, help protect the brain by “eating up” these aggregates and breaking them down. However, recent research suggests that microglia can also “spit out” these protein aggregates again (a process called exocytosis), which contributes to their spread throughout the brain. In this project, I will genetically modify human microglia in a petri dish to include a reporter that allows me to measure exocytosis. I will then use these cells to study why and how microglia exocytose protein aggregates. This research may help identify new strategies to slow or prevent the spread of harmful protein aggregates in the brains of people with Alzheimer’s disease.

  Breaking the Barrier: Mechanically Unlocking Solid Tumors for CAR-T Cell Therapy
  Dr V.J.B van Santen, Academic Center for Dentistry Amsterdam
  Many cancer patients with solid tumors currently benefit little from CAR-T therapy, a promising treatment that works well for blood cancers. The reason is simple: these CAR-T cells often cannot reach the tumor. In this project, I aim to break that barrier. I will investigate whether an existing and safe drug (losartan) can open up blood vessels within tumors, allowing CAR-T cells to better enter and more effectively attack cancer cells. If successful, this could represent a major breakthrough in the treatment of solid tumors. I will test this approach using an advanced 3D laboratory model that mimics tumors and blood vessels. This allows us to quickly and reliably assess whether the strategy works. Ultimately, this research could lead to new, more effective treatments for a large group of patients with solid tumors who currently have limited options.

  Brainstorm: Interferon-ω Dysregulation at the Crossroads of Viral Infection and Neurodegeneration
  Dr L. Bauer, Erasmus University Medical Center Rotterdam
  Interferons are immune signals that help the body fight viral infections, but how they protect the brain remains poorly understood. Recent findings suggest that interferon-omega (IFNω) plays a key role — people lacking IFNω activity can develop severe brain disease after viral infections, indicating it is essential for protection. In this project, I will investigate the role of IFNω both in defending the brain against virus infections and in regulating communication between brain cells. To explore this, I will mimic viral disease of the brain by exposing a human stem cell–derived brain model consisting of specialized cell types (neurons, astrocytes, and microglia) to viruses or IFNω in order to characterize immune responses and neuronal activity. Virus infections in the brain can cause serious illness, long-term damage, and death —understanding how IFNω works could lead to better treatments and prevent complications.

  HYPER-BOND: Maternal stress, fetal movement, and prenatal bonding in hyperemesis gravidarum
  Dr B.N. Ustun-Elayan, University Medical Center Groningen    
  Hyperemesis gravidarum (HG) is a severe form of nausea and vomiting during pregnancy that can have a major impact on women’s physical and emotional wellbeing. Many women feel exhausted, overwhelmed, and struggle to feel connected to their unborn baby during this difficult time. Reduced prenatal bonding may also affect child development later on. Current treatments focus primarily on managing physical symptoms, but do not address this emotional side of pregnancy. This project explores a new way to support women with HG using 4D ultrasound, allowing mothers to see their baby in real time. This may help create moments of connection, strengthen bonding, and reduce stress, even during a challenging pregnancy. If successful, this
  approach could offer a simple way to improve pregnancy experiences for women with HG and may also provide a promising approach for supporting mother-child health in other high-risk pregnancies.

  More than Menstruation: Sex-hormones Controlling Iron Metabolism
  Dr M. Molenaars, Amsterdam University Medical Center
  Iron deficiency is the most common nutritional deficiency worldwide, especially affecting women. This is generally attributed to menstrual blood loss, but non-menstruating rodents show the same sex differences in iron. This project investigates whether estradiol and testosterone actively control how the body stores and uses iron. We will measure iron markers in blood from people undergoing gender-affirming hormone therapy, and test the effects of sex hormones on iron and energy metabolism in human liver cells using multi-omics. If confirmed, this would fundamentally change our understanding of why iron deficiency persists in women. For patients, this matters as iron deficiency is often underdiagnosed and slow to resolve. It could lead to hormone informed treatments that resolve iron deficiency faster, benefiting millions who suffer from fatigue and reduced quality of life.

  Genetic counselling for problematic substance use: Helpful or harmful?
  Dr J.A. Pasman, Amsterdam University Medical Center  
  This project aims to understand whether genetic counselling helps people with substance use problems, or whether it can also be harmful. Psychiatric genetic counselling is new in the Netherlands and previous evidence on its effects is very limited. It is therefore unclear whether giving genetic information will support recovery or unintentionally makes people feel that change is impossible. We will first interview patients who had genetic counselling to identify positive and negative experiences. Next, we will test different ways of communicating genetic risk in an online study in people with substance use problems. Finally, we will combine these findings into a decision tool that can help clinicians choose how to communicate genetic risk. This project is important because it can prevent unintended harm while improving care. By understanding when genetic counselling helps or harms, we can support patients and their families with clearer, safer, and more effective communication.

  Genome-wide quantification of de novo structural variants in human sperm
  Dr W. Höps, Radboud University Medical Center
  Each year millions of children are born with health or developmental problems due to genetic disorders, where parts of their DNA are missing, duplicated, or rearranged. Such mutations often arise during sperm or oocyte formation. We still do not fully understand how often they occur, why certain DNA regions are more affected, or whether some harmful changes remain undiscovered. Studying these phenomena is very challenging, since it requires analysing the complete DNA of thousands of patients. In this project, researchers overcome this problem by introducing novel technology to identify these mutations in sperm cells, which serve as ‘virtual’ offspring genomes. This will lead to the first complete human map of where and how often these DNA changes occur and provide crucial insights into the biological processes leading to disease. Thereby, the research will enable critical advances in understanding and diagnosing the related disorders.

  InnerMuscle: Deciphering the crosstalk between muscles and nerves in advanced 3D models
  Dr C.M.S. Philips, Maastricht University
  Incomplete recovery after facial nerve injury can lead to loss of muscle control, impairing fundamental expressions such as smiling and speaking. The underlying mechanisms remain poorly understood due to a lack of relevant in vitro models. This project will develop advanced 3D systems that replicate the craniofacial neuromuscular axis. Facial muscle constructs will be created within a biomimetic ECM-based hydrogel, while motor and sensory neurons are guided through engineered channels to form targeted connections. The platform will enable controlled study of denervation and competitive reinnervation, assessing innervation patterns and molecular responses. In this way, this versatile system will accelerate therapeutic target discovery, support high-throughput drug screening, and offer a powerful tool for investigating broader neuromuscular disorders, ultimately informing strategies to restore function and quality of life of patients with facial palsy.

  3D neuromuscular junction modelling to study contraction induced synapse fragility in Duchenne
  Dr R.G. Goossens, Leiden University Medical Center
  In Duchenne muscular dystrophy, muscles weaken because they cannot repair the damage that builds up during everyday contractions. We want to understand whether the nerve–muscle connection (the neuromuscular junction, NMJ) breaks because the muscle is already fragile, or whether NMJ problems themselves help drive this weakness. To study this, we will create small three-dimensional human muscle tissues with motor neurons so they form working NMJs. We will gently activate and stretch these tissues to see how normal and “stretch while contracting” movements affect strength and nerve–muscle signaling, comparing healthy and Duchenne samples. This model can later be used to test medicines that protect the NMJ. If strengthening the NMJ helps preserve muscle function, patients may remain mobile longer, and this system can also speed up testing of new treatments while reducing animal use.

  Do Suicidal Crises Have Tipping Points? A Real-Time Test Using Digital Monitoring
  Dr J.S. van Bentum, Utrecht University
  Suicide has major consequences for individuals and their loved ones. Suicidal crises often seem to emerge suddenly, but we still do not fully understand how this happens. This project investigates a new explanation: that a crisis arises as a tipping point, where thoughts and feelings suddenly shift. We will follow people at increased risk of suicide over several weeks using brief questions on their smartwatch. This allows us to track changes in thoughts, emotions, and behaviour from moment to moment. We will examine whether early warning signals precede such shifts. This may help to identify vulnerable moments earlier. This is important for patients and their loved ones, but also for therapists, as it may help them respond more effectively to emerging crises and provide more targeted treatment.

  From Level to Change: Rethinking Reproductive Mental Health Through Neurosteroid Dynamics
  Dr L. Rösler, Netherlands Institute for Neuroscience
  Women are twice as likely as men to develop depression — yet the hormonal mechanisms behind this vulnerability remain poorly understood. Millions experience severe mood disturbances and sleep problems during reproductive transitions, representing a major and largely unmet public health need. We may be looking at the wrong signal. By focusing almost exclusively on hormone levels, current research may have overlooked a more critical driver: how rapidly hormones change. This project tests that idea by tracking hormones, sleep, and mood daily across the menstrual cycle in real life — linking rapid hormonal shifts to disruptions in sleep and mood to examine whether the rate of change, rather than the level, drives risk. If confirmed, this would enable earlier identification of vulnerable women and better-timed interventions in clinical practice, reducing the burden of depression, anxiety, and sleep disorders at key moments in women's lives.

  IMMERSE: A CRISPR-Cas9 screening platform for immunometabolic discovery in primary human macrophages
  Dr F Vrieling, Wageningen University and Research 
  Our immune system protects us from harmful invaders. However, an overactive immune system can also be harmful, leading to inflammation and contributing to conditions such as heart disease and obesity. We know that the way immune cells use energy, also called their metabolism, strongly affects how they function. However, we do not yet understand how to guide this in disease. With this project, we aim to find new genes and processes that regulate metabolism in specific immune cells called macrophages. These insights may help develop future treatments that either reduce harmful inflammation or strengthen the immune system in patients who need it. We will make use of CRISPR-Cas9 technology, a precise tool that allows us to switch genes on or off in human macrophages. By testing many genes in a systematic way, we hope to find the most important ones that govern immune cell metabolism so they can be studied in more detail.

  The Midnight Factory
  Dr W. Kholosy, University of Amsterdam
  Gene therapies offer life-saving cures for diseases once considered incurable, such as cancer. Yet, their extreme cost limits global patient accessibility. The primary bottleneck is the inefficient manufacturing of viral vectors. Current industrial systems rely on toxic antibiotic-based switches that trigger a "metabolic collapse" in producer cells, killing the factory before the work is finished. I will develop the “Midnight Factory,” using melatonin, a natural hormone and powerful cellular protectant, to control viral vector production. I have engineered a synthetic receptor that repurposes melatonin as a precision induction trigger. Unlike toxic triggers, Melatonin acts as an "Active Shield," protecting the cells’ energy centers (mitochondria) during production. This project will validate the system in animal-free (NAMs) conditions to increase yields tenfold, transforming expensive medical breakthroughs into affordable, sustainable treatments for all patients

  From polygenic scores to regulatory profiles: Evaluating sequence-based AI in human β-cells
  Dr A.J. Claringbould, Erasmus University Medical Center
  Type 2 diabetes is influenced by many genetic factors but we still do not fully understand how these genetic risks affect the development of disease. One hypothesis is that certain genetic combinations may change the function of insulin-producing cells in the pancreas, but this has not been proven. In this project, I will test whether new AI tools can predict what genetic differences might do inside human insulin-producing cells. First, I will use AI to estimate how small DNA changes could alter gene activity. Then, I will combine these effects to build a molecular profile for each person in a large diabetes study. Finally, I will test the AI’s predictions in insulin-producing cells grown from patient blood samples. This novel approach could reveal how genetic risk shapes the behaviour of insulin-producing cells, opening entirely new directions for understanding diabetes that could guide future personalised treatments.

  JOINT2BRAIN: Deciphering Joint-to-Brain signaling in Osteoarthritis
  Dr V.P.G. Joris, Maastricht University
  Osteoarthritis (OA) is a common joint disease that causes pain, stiffness, and reduced mobility, with a major impact on daily life and quality of life. Many people with OA also experience depression, but the biological link between joint disease and mental health is still poorly understood. The JOINT2Brain project will study whether molecules released by osteoarthritic joint cells can travel through the body and affect the brain, potentially contributing to depression. Using advanced cell culture models mimicking communication between the joint and the brain, the project will explore how OA may influence brain function and potentially participate to the onset of depression. This research could lead to new ways to better understand, diagnose, and treat both the physical and mental effects of OA, ultimately enhancing patients' quality of life.

  Mapping M-Cell fate decisions: AI-driven cell tracking in a reconstructed Intestinal-stromal niche
  Dr S.E. ELI, AMOLF
  M cells line the intestinal wall and capture microorganisms from the gut, activating the immune system. Fine-tuning their numbers holds promise for improving oral vaccines and understanding intestinal inflammatory conditions. However, we do not yet understand how M cells form, and current laboratory models fail to reproduce this process faithfully. This project introduces a novel platform: a miniature intestinal tissue built in a dish, where gut organoids are combined with stromal cells that deliver signals in a spatially controlled way, mimicking how the body naturally instructs M-cell formation. Using live imaging and AI-assisted tracking, I will follow individual cells over time and space as they become M cells. In parallel, protein profiling will reveal the molecular signals exchanged between cell types. This platform will provide a new tool to test strategies that tune M-cell numbers, directly relevant for oral vaccine development and intestinal disease.

  Targeting cell-surface RNA to modulate immune recognition
  Dr Z. Li, Utrecht University
  Cancer immunotherapy often targets molecules on the cell surface, but many of these are also present on healthy cells. This can cause harmful on-target, off-tumor side effects. In this project, I want to test a new idea: using cell-surface RNA (csRNA) as a more selective target. Our recent work and early unpublished data suggest that csRNA may be more abundant on tumor cells than on normal cells. I hope to show that csRNA can be used in two ways: to recruit natural killer (NK) cells to tumor cells, and to weaken inhibitory signals that reduce NK-cell killing. If successful, this project could open a new route to safer and more selective cancer immunotherapy. I will do this by building RNA-binding proteins that can guide NK cells to tumors, identifying the RNA molecules they bind, and testing these strategies in cell-based assays that measure tumor killing and effects on normal cells.

  Localising the leak in patients with spontaneous intracranial hypotension (LEAP)
  Dr O.A. Berkhemer, Amsterdam University Medical Center
  Patients with spontaneous intracranial hypotension have a tear in the membrane around the spinal cord, causing cerebrospinal fluid to leak. Finding this tear requires burdensome procedures: lumbar puncture, contrast injection and radiation. Despite this, the leak is often not found, especially in the upper back. We want to detect the leak using an MRI technique originally developed to measure blood flow in the hearts of unborn babies. This technique measures flow in three directions within a large volume and is resistant to motion — exactly the properties needed to find a small, fast leak in the spine. We will scan approximately 40 patients and compare results with current diagnostics. If successful, a 10-minute MRI scan — without puncture, contrast or radiation — could replace current invasive procedures, making diagnosis more accessible and less burdensome for these severely ill patients.

  HiT-PAIN: HIgh Throughput Pluripotent stem cells-derived Augmented In-vitro Neuronal model
  Dr A.B. Bortolin, Maastricht University
  Pain affects millions of people worldwide, yet many patients lack effective treatments. Current drug-testing platforms rely on animal cells or artificial stimulation that poorly reflects how pain works in humans. HiT-PAIN will build the first fully human, high-throughput platform for testing pain drugs. Using human stem cell-derived sensory neurons activated by light rather than electrodes, we mimic how pain signals naturally arise and test thousands of compounds simultaneously with automated imaging.This approach is faster, more human-relevant, and entirely animal-free — directly supporting the EU's strategy to phase out animal use in preclinical research and accelerate the transition to human-based testing. For patients, this means better and faster routes to effective pain relief. For science, it means a new open platform that other researchers can use and build upon, for patients it means a better and faster route to effective pain relief.

  Pregnancy as a Stress Test: Unmasking Hidden Weaknesses in Blood Vessels
  Dr J.M.E. Tan, Amsterdam University Medical Center 
  During pregnancy, the mother’s blood vessels are placed under extreme strain. In high-risk pregnancies, such as those complicated by pre-eclampsia, we can observe damage in the blood vessels of the placenta. These changes resemble early stages of atherosclerosis, but instead of developing over decades, they appear within just a few months. I propose that studying this damage in placental arteries can provide a model of accelerated atherosclerosis and reveal hidden weaknesses that may help explain the increased risk of heart disease later in life. The placenta, which is usually discarded after birth, may therefore contain early warning signs about a woman’s future cardiovascular health. In this project, I will use advanced techniques to study the cells in placental blood vessels to understand these changes and how they relate to later heart disease risk, with the aim of improving early detection and prevention.

  RememberMe: A Synaptic Census of the Hippocampus in ME/CFS
  Dr F.C.S. Correa da Silva, Netherlands Institute for Neuroscience
  Myalgic encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a serious disorder with an unknown cause. People with ME/CFS experience symptoms such as extreme fatigue after activity (post exertional malaise), sleep and memory problems, suggesting that the brain may be involved. I aim to understand whether cognitive symptoms are linked to alterations in synapses - the connections between brain cells. I will focus on the hippocampus, a part of the brain that plays a key role in memory and thinking. Using brain tissue from people with ME/CFS, I will study these synapses in detail. This includes looking at how many there are, their composition, and how they function, using advanced microscopy techniques and by measuring gene activity related to their function. This work could uncover a new biological explanation for the cognitive difficulties experienced by people with ME/CFS and other post acute infectious syndromes.

  REVIVE: reactivating regenerative capacity in the adult human heart through mechanical unloading
  Dr V.M. Pinto, University Medical Center Utrecht
  Heart diseases are a leading cause of death worldwide because the human adult heart is not able to repair itself after damage. However, recent studies suggest that when subjected to reduced mechanical forces, the heart may regain some ability to recover. In this project, I want to understand if reducing the workload in heart tissue, similar to what happens in patients supported by a mechanical heart pump, can reactivate regenerative processes. I aim to identify signals that help heart cells divide and grow and restore damaged tissue, as this could open the door to new treatments that help the heart heal itself. To do this, I will study small living slices of human heart tissue obtained from donor and patient hearts. These samples will allow me to test, in a controlled laboratory environment, how changes in mechanical stress affect heart cells. Ultimately, this research may lead to new therapies that improve the recovery and quality of life of heart failure patients and their families.

  Electrical Impedance Tomography Guided Ex Vivo Lung Perfusion Management
  Dr P. Blankman, University Medical Center Utrecht
  "Lung transplantation is the only treatment for patients with end-stage lung disease, but there is a severe shortage of suitable donor lungs. Ex vivo lung perfusion allows lungs to be extensively tested and optimized, increasing the number of suitable donor lungs. Currently, all lungs are treated the same way during lung perfusion. In this project, we aim to use electrical impedance tomography (EIT) to better understand the ratios of lung ventilation and perfusion in donor lungs to enable targeted treatment. With targeted treatment, we can improve lung function, increase the number of suitable donor lungs, and reduce mortality on the transplant waiting list.
  The project involves the development of EIT electrodes suitable for use on lung tissue. Ventilation is continuously measured using the measured electrical resistance. Blood flow is measured during a breath hold. The measurements are compared with CT as the gold standard."

  CHECK-IT Stroke: when cancer immunotherapy unmasks hidden stroke vulnerability
  Dr A.M. Algra, Erasmus University Medical Center Rotterdam
  Immunotherapy has greatly improved cancer treatment. However, some patients develop problems in the brain such as stroke, changes on brain scans, and memory complaint. It is unclear why this happens. I want to study whether these problems are linked and whether treatment reveals a hidden vulnerability in the brain’s blood vessels. I will use data from about 4,000 patients treated with immunotherapy between 2016 and 2024 in four hospitals. I will study when these problems occur, how they are related, and whether we can identify patients at higher risk beforehand. This project aims to better understand which patients are vulnerable. This is important for patients, their families and doctors, as it may help guide treatment decisions, improve monitoring, and reduce unexpected complications during therapy.