Nine UMC Utrecht teams receive ZonMw grant

Onur Başak (UMC Utrecht), Noelia Antón Bolaños (UMC Utrecht) & Stefan Barakat (Erasmus University) 

About 15% of children and adolescents worldwide are affected by neurodevelopmental disorders (NDDs). These conditions often show overlapping symptoms, like impaired speech, behavioral problems, and epilepsy. On the other hand, symptoms of individuals diagnosed with the same NDD can differ broadly between individuals. This makes it difficult to understand the underlying causes of NDDs and to develop effective treatments. 

Recent research suggests that DNA packaging by chromatin, which regulates gene activity and genome organization, plays an important role in the onset and progression of NDDs. SETD1A and SETD1B regulate key aspects of this process, which is why this research team will investigate how these genes contribute to the wide range of NDD symptoms. 

They will use patient-derived stem cells to grow human brain cells. Using advanced molecular and functional analysis methods, they will study how variations in SETD1A and SETD1B genes affect neuron development and lead to different disease patterns. The findings will improve our understanding of NDDs and support the development of more personalized and effective treatments. 

András Spaan (UMC Utrecht) & Reinout van Crevel (Radboud UMC), on behalf of the team of UMC Utrecht (Marjolein Hensgens, Olaf Cremer, Bart Bardoel & Anita Schürch) & Radboud UMC (Jaap ten Oever, Mihai Netea & Ilse Kouijzer)  

Staphylococcus aureus bacteremia (SAB) is a serious bloodstream infection that can range from mild illness to life-threatening conditions such as sepsis. It remains unclear why some patients become severely ill while others do not. 

The ENDO-SAB project investigates whether differences in the body’s inflammatory response, so-called endotypes, can explain this variation. While endotypes are known to be important in other infections, they have not yet been studied in SAB. 

To investigate this, the researchers will study large groups of patients using advanced techniques to map immune responses at the molecular level. They will identify distinct immune endotypes, link them to clinical outcomes, and investigate the genetic and autoimmune factors that shape them. 

This approach will improve understanding of why SAB affects patients differently, support earlier identification of high-risk patients, and help pave the way for personalized treatments, including targeted immune therapies. 

Jeroen Pasterkamp (UMC Utrecht), Hans van Bokhoven (Radboud UMC) & Rick Wansink (Radboud UMC) 

Myotonic dystrophy type 1 (DM1) is a hereditary muscle disease, caused by a genetic defect in DNA. This defect leads to abnormal folding and accumulation of certain RNA molecules, resulting in problems with muscle function.

Current research into DM1 has mainly focused on muscle pathology, but there are also indications of abnormalities at the connection between nerves and muscles (the neuromuscular junction). However, the underlying mechanisms remain unclear.

In this project, researchers will develop new models using patient-derived stem cells. These models allow them to study the neuromuscular junction of patients with DM1. In addition, the researchers will investigate whether the abnormalities can be rescued.

Ultimately, the researchers aim to gain more insight into how DM1 affects both muscles and the nervous system. This may also support the development of new treatments, without the need for animal testing.

Onno Kranenburg (UMC Utrecht), Jeroen Hagendoorn (UMC Utrecht), Martijn Gloerich (UMC Utrecht) & Gijsje Koenderink (TU Delft)

Cancer is one of the leading causes of death worldwide. Patients usually die as a result of the formation of metastases. Current research into how metastases behave mainly focuses on genetics, cell biology, and immunology.

However, tumor cells also experience various mechanical forces, such as the pressure of surrounding tissue. This occurs both in the primary tumors and during metastasis to other organs. The tumors respond to these forces by activating survival programs, which results in more aggressive behavior.

Even temporary mechanical forces can cause long-lasting changes in behavior. This phenomenon is called ‘mechanical memory’. Previous research from this team provides strong indications that the mechanical memory of colon cancer cells is activated during metastasis to the lungs.

Theo van den Broek (UMC Utrecht), Virgil Dalm (Erasmus MC, coordinator), Ines da Silva Serra (Erasmus MC), Serge Dumoulin (Spinoza Centre for Neuroimaging) & Marlou Kooiker (Erasmus MC)

People with complex inborn errors of immunity (IEI) typically suffer from infections, autoimmune diseases, and malignancies. However, these disorders may also present with other symptoms, such as neurodevelopmental disorders. These manifestations still receive little attention, because they appear to be less immediately life-threatening.

The IMBRAIN project aims to better understand these symptoms by focusing on one IEI (APDS). The goal is to understand how brain and behavioral abnormalities develop in APDS and whether these can be prevented or treated.

To do this, the researchers will use a translational approach combining mouse models, brain scans, and blood tests. They will also use a mobile app to study learning, behavior, and brain structure. In addition, they will test an existing drug for APDS (leniolisib), which may help restore both the immune system and brain function.

This research could lead to better recognition of symptoms, more targeted treatments, and reduced stigma. It also highlights that IEI affects the entire body and requires a broader approach to care.

Boudewijn Burgering (UMC Utrecht) & Maike Hansen (Radboud University)

Complex organisms, such as humans, arise from a small group of identical cells that gradually develop into many different cell types. This process requires cells to make very precise decisions about their fate. If this goes wrong, it can lead to severe developmental disorders. Traditionally, these conditions are explained by genetic mutations, but new research suggests that non-genetic factors can also play an important role.

Recent research shows that random fluctuations in gene activity (gene expression noise) play a key role in the decision of a cell to transition to a new cell identity.

In this project, the researchers investigate how cells regulate this noise, how this is used to guide changes in cell identity, and how this ensures proper development. Using advanced single-cell technology, the researchers measure noise for the first time directly at the protein level and identify the factors that drive this process.

By uncovering how noise is controlled, the researchers aim to discover new mechanisms involved in both healthy embryonic development and the onset of disease.

Marianne Verhaar (UMC Utrecht), Martijn Koppens (WKZ/UMC Utrecht) & Jeroen de Baaij (Radboud UMC Nijmegen)

Kidney tubulopathies are a group of genetic kidney disorders in which the kidney tubules do not function properly. There are currently no effective treatments for these diseases.

Mitochondria are the cell’s powerhouses and play a key role in energy production. This is especially important in kidney tubules, which require large amounts of energy for ion transport; the movement of charged particles in and out of cells.

Recent studies show that mutations in mitochondrial DNA may be more common in kidney tubulopathies than previously thought. However, research has been limited by the lack of accurate lab models and the difficulty of modifying mitochondrial DNA.

The REPAIR project brings together multiple areas of expertise to address this problem. Researchers use kidney models based on patient cells and apply advanced gene-editing techniques to correct mitochondrial DNA mutations. They then study how this affects ion transport in kidney tubules. This approach will improve understanding of the disease, support better diagnostics, and help pave the way for future treatments.

Saskia van Mil (UMC Utrecht) & Denise Okafor (Penn State University)

The liver uses specialized proteins, called nuclear receptors, to regulate how the body stores and uses fats and sugars. Three key receptors (FXRα, LXRα, and PPARα) are important drug targets for treating metabolic diseases such as diabetes and high cholesterol. However, current drugs often cause unwanted side effects.

For a long time, these receptors were thought to function only by partnering with another protein called RXR. However, recent research has shown that FXRα can also act independently of RXR. It can pair with itself and bind to different regions of DNA, activating a different set of genes than when it binds to RXR. This shows that nuclear receptors are more flexible and complex than previously believed.

In this project, researchers will investigate how often these alternative binding modes occur, how they affect liver function, and whether these interactions can be controlled to develop safer and more effective treatments for metabolic diseases.

Annemieke Dols (UMC Utrecht), Edwin van Dellen (UMC Utrecht), Karel Scheepstra (Amsterdam UMC), Linda Douw (Amsterdam UMC), Philip van Eijndhoven (Radboud UMC) & Inge Huitinga (Netherlands Institute for Neuroscience)

Our brains are not fixed but can adapt. For instance, they can form new connections between nerve cells. This ability is called neuroplasticity and is important for recovery from several psychiatric illnesses, such as schizophrenia and depression.

Electroconvulsive therapy (ECT) is currently one of the most invasive treatments that can boost neuroplasticity and thereby treat psychiatric illnesses. During ECT, a brief electrical pulse triggers a controlled seizure in the brain. Although ECT is highly effective, researchers still do not fully understand the changes it produces in the brain. This project aims to investigate how ECT affects the brain across multiple levels.

The researchers will use brain scans in patients receiving ECT to measure changes in brain structure, function, and connections. They will also study donated brain tissue from people who received ECT to look at changes on a cellular level. By combining these approaches, the researchers aim to identify biological markers that explain how ECT works and improve psychiatric treatments.