15 innovative ideas receive Off Road grant

Improving oncologic PET imaging using a new method to quantify arterial radiotracer levels
Dr ir R. Wierts – Maastricht UMC+

At present, Positron emission tomography (PET) plays a key-role in many oncologic applications. Quantification of PET radiotracer uptake has been shown to improve PET image interpretation. However, the current method of PET quantification used in clinical routine suffers from important shortcomings resulting in inter-patient and therapy-induced variations in tumor radiotracer uptake. This results in a decreased diagnostic accuracy and may even lead to erroneous interpretation regarding the efficacy of oncologic treatment. 

The aim of this project is to eliminate these variations, and therefore enhance PET quantification, by correcting for the total amount of radiotracer available to the tumours using a highly innovative, non-invasive technique to measure radiotracer levels in the arterial blood, compatible to the current clinical workflow. This will result in improved personalized patient management from which patiens will directly benefit.

Immune tolerance of valve transplants: Translating prenatal protection mechanisms from womb to heart
Dr M.C. Peters – Technical University Eindhoven (TU/e)

Children born with defect heart valves often receive a donor valve that needs to be replaced multiple times throughout life as this valve cannot grow and can elicit immune rejection. A perfect example of tissue that is not rejected by the immune system is a baby in it’s mother’s womb, even though the baby is for 50% made up of the father's genes. In this study, we are testing whether we can apply this principle of protection to transplantation through the investigation of the trophoblast cell: the cell that is responsible for the immune-tolerant environment in the womb. We investigate this by delivering the trophoblast specific genes in heart valve cells and by bringing these trophoblast cells directly into contact with the heart valve. By placing the valve in a system where immune cells can flow over the valve we will test whether there is immune rejection. Our goal is to improve durability of the transplanted tissue and limit the need for reoperations in these young children.

Divide and conquer: cyst clonality and initiating factors
Dr L. Louzao Martinez – Leiden University Medical Center (LUMC)

Polycystic Kidney Disease, characterized by the progressive increase in fluid-filled cysts, is thought to start as a focal disease upon inactivation of the PKD1 gene in single cells. It is not clear whether initial PKD1-/- cells compete and overgrow PKD1+/+ cells, and how cystic cells exert their cystogenic effects on the microenvironment. By studying the confetti-reporter in an inducible Pkd1-/- mouse model and in PKD tubuloids, this project applies an innovative strategy to study clonality of cysts. In addition, knowledge will be gained about secreted factors critical in initiating the transformation of epithelial cells into ‘cyst-epithelial’ cells, thereby revealing potential targets for future therapy.

Bug2drug: innovative microbiome-phenotyping platform for personalized colorectal cancer treatment
Dr N. van Best – Maastricht University

Colorectal cancer is a major cause of mortality worldwide. Response to palliative irinotecan treatment is variable and gastrointestinal toxicity common. Intestinal bacteria are in part responsible for these adverse effects. Microbiota manipulation to prevent irenotecan-induced gastrointestinal toxicity holds promise, but tools to examine the bacteria involved in drug metabolism are currently lacking. Here, we aim to develop a proof-of-principle for a novel drug toxicity platform. We will use special fluorescent probes targeting anticancer-drug metabolizing microbes in the human gut, and we will sort and characterize these bacteria.

U-OK SNM - Ultrasound for Obtaining Knowledge on Sacral Neuro Modulation
Dr A.T.M. Grob – University Twente

Fecal incontinence (FI), the fear of suddenly losing your stool at work or during dinner at a restaurant, has a major negative impact on the quality of life and leads to reduced participation in society and loneliness. There are some non-surgical options such as using an anal tampon or manual anal irrigation to empty the last part of the rectum. If conservative treatment is insufficient, surgical treatment by Sacral NeuroModulation (SNM) can be considered, in which a pacemaker like device is placed to improve fecal continence. 
The results of this SNM treatment (at least 50% improvement in complaints in approximately 70% of patients) are quite promising. However, no one really understands how SNM works. By using functional ultrasound on patients before and after SNM, I hope to gain more insight into the mechanism behind SNM and its effect on the muscle function of the anal sphincter. In time this will enable more targeted counseling, optimalisation and cost-effective treatment of FI.

Exploring the brain’s dura mater membrane and its immunological context in brain cancer
Dr M.G. Best – Amsterdam UMC

Glioblastoma is a severe type of brain cancer with a dismal prognosis. Despite increasing knowledge on brain tumor biology, in the past 20 years no new treatment options have been identified. The view on brain cancer should be broadened. Historically, the dura mater was only seen as a physical barrier enclosing the central nervous system. More recently it has been shown that the dura mater is an immunological active hub, involved in brain inflammation and cancer. At least, that was shown in murine models. Thus far, knowledge on dura mater biology in humans is limited.In this project I will investigate the dura mater on a detailed single cell level in patients with and without a malignant brain tumor that are subjected to brain surgery. I expect to identify a difference in composition, characteristics and intercellular communication in the cells of the dura mater of these patients. Knowledge from this work will guide further research to exploit these cells to target glioblastomas.

Why do oligodendrocyte precursor cells not repopulate the irradiated brain?
Dr L.E. Kuil – NKI

A significant number of brain tumor patients receiving radiotherapy develop cognitive impairment associated with white matter loss. Our research in animal models has revealed that a specific type of glia, important for white matter, is highly sensitive to radiotherapy and disappears. However, in the adjacent  non-irradiated areas these cells are still present, yet they fail to repopulate the irradiated brain. Why this does not happen is unknown. My hypothesis is that these cells are dysfunctional, preventing repopulation. By using a genetic model I can specifically remove most of the remaining cells, which I expect to stimulate the remaining cells to expand and repopulate the irradiated brain. This research will give insight in the mechanism of glial recovery and identify new therapeutic targets to preserve white matter in future radiated patients.

The road towards photo switchable anti-TNF-alpha antibodies for the treatment of psoriasis
Dr V.F.M. Ornelis – Maastricht University

In this project we will perform the first steps towards photo switchable antibodies for the treatment of psoriasis. Psoriasis is an autoimmune disease in which chronic inflammation of the skin takes place. Current medication consists out of antibodies against TNF-alpha (TNF-alpha inhibitors) amongst others. The problem with TNF-alpha inhibitors is that it renders the patient more susceptible towards infections. This is because current TNF-alpha inhibitors suppress the immune system through the entire body and not only at the sites of psoriasis related inflammation. In this project we will perform the first steps towards a TNF-alpha antibody that can be turned on or off using visible light. This way, the sites of psoriasis related inflammation can selectively be irradiated which will locally activate the antibody. This will inhibit the immune system locally instead of through the entire body as is now the case. As such, the risk towards infections is prevented.

Pre-Trained Brain Organoids: A Novel Approach to Neural Repair
Dr J. Wang – University of Amsterdam

Transplantation of brain organoids has been proposed as a possible treatment for brain injury. However, all current research so far has considered brain organoids as a passive element purely adapting to the host. Here I will test the hypothesis that brain organoids might also, in turn, modify neural activity in the host brain. This is an essential first step to eventually devise novel therapies to restore cognitive functions following brain injury, by pre-training brain organoids to perform certain forms of processing before transplantation. To test my hypothesis, I will use a bioelectronic approach to train brain organoids to generate specific firing patterns, and then combine large-field two photon imaging with behavioral tasks to study if transplanted organoids can influence ongoing visual processing in the host. If successful, this project will provide a new avenue to use bioelectronic trained brain organoid transplantation for brain repair.

Modelling early social behaviour - do cerebellar interneurons shape social network development?
Dr I. da Silva Serra – Erasmus MC

Social behaviour is essential for development, well-being and survival. In a number of disorders, such as anxiety or neurodevelopmental disorders, social behaviour is affected. This reduces quality of life and people's participation in society. Although we know much about the social adult brain, not a lot is known about how it develops in infancy. Currently, mice are still widely used to study the mechanisms of human behaviour and disease. However, very young mice are very difficult to work with and most current neuroscience tools cannot be used in such small animals. In this project, I will develop new tools that will enable me to follow the development of the social brain over time as well as manipulate neuronal function to understand which brain neurons coordinate social behaviours. If successful, this project will change the way we study developing social behaviours and can provide new platforms to study therapy effects in early stages of disease.

Novel antigen discovery to eradicate human hookworm infections
Dr R.A. Murugan – Leiden University Medical Center (LUMC)

Hookworm infection, one of the major neglected tropical diseases, causes severe blood and protein losses in young children and pregnant women in low- and middle-income countries, hampering physical and cognitive development. Yet, no licensed vaccines are available to date. Human clinical trials using whole larvae immunization achieve some protection, but what generates this protection remains unknown. This project aims to uncover responsible hookworm vaccine targets by creatively combining state-of-the-art technologies in B cell immunology and parasite biology. Using uniquely available human clinical trial samples, hookworms from infected humans and expertise on single B cell/monoclonal antibody generation platform, I will develop a holistic strategy and identify hookworm antigens targeted by protective antibodies. Exploring the discovered antigens as vaccine candidates will lay a clear blueprint for attaining protection to eradicate hookworm infections.

Rethinking Chronic Disease Treatment via Inverse Hormesis with Pulsing
Dr F.P. Chilunga – Amsterdam UMC

Chronic diseases like high blood pressure and diabetes are a major concern, as many people find it difficult to take medication every day and for a long time. To tackle this, I am exploring a new approach involving slightly higher, yet safe, doses of medication given with breaks in between to promote the body's natural healing. By studying this approach in the lab and analyzing previous research on magnetic energy treatments, I aim to show that it's possible to develop medications that are not taken all the time but yet effectively treat these widespread conditions. My research could potentially revolutionize healthcare by introducing treatments that don't require daily medication and even reverse the disease, improving the lives of countless individuals worldwide and reducing healthcare costs

Supercharging oncolytic human adenoviruses by targeted proteolytic degradation
Dr K.R. Rafie – University of Groningen

Cancer is one of the top killers in the world with up to 1 in 4 deaths being caused by it. Therefore, it is of utmost importance to develop novel avenues to combat cancer. Here we aim to utilise oncolytic human adenoviruses, which are viruses that have been altered to recognise and kill cancer cells in a safe and concerted manner. However, their efficiency still needs to be increased to make them a general use therapy to combat and cure cancer. To achieve this, we further want to identify and develop novel small molecule drugs that can significantly increase the potency of these oncolytic viruses, which has the tremendous potential to ultimately lead to a faster and complete eradication of cancerous tissues, whilst significantly reducing the chance of side-effects which are common among other types of cancer therapies. We believe that this approach has the potential to significantly improve the life of patients currently suffering from cancer through this novel treatment method.

Pathways for restoration of walking capacity after stroke (PATHWAYS)
Dr S.B. Zandvliet – Erasmus MC and Radboudumc 

Restoring walking capacity is crucial to regain independence after a stroke in which rehabilitation plays a vital role. To design an individual rehabilitation program, prediction models of recovery are essential. Current models for recovery of walking capacity falsely focus on intactness of the cortical spinal pathway for motor output while the reticulospinal pathway is largely ignored. The reticulospinal pathway innervates muscles close to the body, such as the gluteal muscles. These muscles are very important for maintaining balance while walking. The PATHWAYS project will use an innovative combination of methods to investigate the reticulospinal pathway in relation to walking capacity in people after a stroke.

Robotic Implant System for Enhancing Urination (RISE-U)
Dr  I. Tamadon – University Twente

Over 200 million people worldwide suffer from Urinary Incontinence (UI) that is twice as high in older women as in older men. UI is also a common condition in the Netherlands, with a prevalence of 36.8% in adults. The functionality of the urinary system depends in turn on the proper functioning of the individual organs that compose it.
In this context, RISE-U aims to provide a modular solution for patients with UI, which is based on the combination of various engineering fields (bioengineering, mechanic, electronic, material, and computer) to restore the correct functionality. In this paradigm, a novel implantable device will be interfaced with an external control like a smartwatch, allowing the patient to monitor and control the system. The proposed device is able to harvest energy from the urine flow in the beginning phase of voiding and accelerate it in the end. The harvested energy will be utilized in the low power electronics for volume sensing, communication and sphincter control.