ISCOMS Research Fellowships

Supervisor: Lydia Visser MD PhD

Field of research: Pathology and Medical Biology

Description: We will look at different aspects of lymphoma research by looking at the expression of proteins, drug sensitivity, combination therapy, or effect on the micro environment. We can use techniques such as immunohistochemistry, cell culture, flow cytometry, western blot, ELISA, and metabolic assays.

Supervisor: Prof. Henri Leuvenink MD PhD, Cyril Moers MD PhD

Field of research: Surgery

Description:Organ transplantation is a lifesaving therapy for patients suffering from end-stage organ failure. Due to the growing success of transplantation, more patients are on the waiting list and more donors are needed. This leads to an increasing percentage of poor-quality organs. In the Surgery Research Lab researchers are trying to find new therapies to reduce or repair the injury by using machine perfusion techniques accompanied with pharmacological intervention.

The IRF student will be involved in a project in which protective treatments during perfusion will be administered to ex vivo perfused porcine kidneys. The IRF student will work together with a PhD student and will get full insight into the principles of machine perfusion. A laboratory introductory course will be part of the research stay. Depending on the progress and experience of the student, a sub-project will be designed.

It is mandatory for the IRF student to follow the Transplantation Medicine Summer School which will take place in the first days of the IRF period:

http://www.rug.nl/gradschoolmedicalsciences/informationfor/summerschools/transplantationmedicine/index

Supervisor: Romana Schirhagl

Field of research: Biomedical Engineering

Description: Free radicals are ubiquitous chemical species that play important roles in both health and disease. It is, therefore, vital to know where, when, and in what quantities they are produced in cells and tissues. However, free radicals are usually rather short-lived and their steady-state concentrations in the cell are relatively low, which poses a challenge for their detection.

In this project we will use a novel method for free radical detection – diamond relaxometry. We will bring diamond nanoparticles hosting specific defects of crystal structure – nitrogen-vacancy (NV) centers – inside live cells. Fluorescence of NV centers depends on their quantum state, which, in turn, can be manipulated and read out optically, using a green laser. Moreover, this fluorescence is highly responsive to the local concentrations of paramagnetic species, such as free radicals. This method has outstanding sensitivity and selectivity, allowing us to record the signal from extremely low concentrations of free radicals.

When the nanodiamonds are internalized by the cells, we will use these properties of NV centers to determine the intracellular concentration of free radicals. We will then use complementary techniques, such as immunostaining and confocal microscopy, to get additional information on the biological characteristics of each individual cell – e.g., its differentiation status. We will correlate the free radical load as measured by diamond relaxometry with the biological context on the single-cell level.

Supervisor: prof. dr. Ute Bültmann

Field of research: Social Medicine

Description: A considerable number of adolescents (i.e. 10 to 25%) has to deal with the burden of mental health problems, and these problems often track into adulthood. Mental health problems comprise various emotional and behavioral problems (e.g., depressive symptoms, anxiety, aggressive and delinquent behavior). Adolescents’ mental health problems can have long lasting negative consequences, as they may have a negative effect on the transition from school to work. Adolescents suffering from mental health problems are at risk of
dropping out from high school, and when entering adulthood, to be unemployed and earning lower wages.

Finishing a study and finding a job are major markers in young adulthood.Especially today, where starters at the labour market and young working adults have to earn a living in a new world of work (e.g. more temporary work, multiple jobs) with transformed labour markets (e.g. more self-employment and a 24/7 work cycle in a global economy). The school-to-work transition into a new world of work evidently challenges mental health. Therefore, the aim of the NWO Vici-project ‘Today’s youth is tomorrow’s workforce: generation Y at work’ is to examine the complex relationship between mental health and work from childhood to young adulthood, using a life course perspective.

Unique data from the TRAILS study (TRacking Adolescents’ Individuals LivesSurvey) with 18 years of follow-up will be used to ans wer relevant research questions. TRAILS is a Dutch prospective cohort study, and follows 2300 children from the age of 10/11 years into young adulthood, currently 28/29 years. An overview of available data of the TRAILS study can be found at the website (www.trails.nl). The specific research question for the IRF student will be determined – in consultation with the student – at the start of the IRF project.

Supervisor: dr. Sebo Withoff

Field of research: Genetics ERIBA

Description: The Immunogenetics group of the Department of Genetics within the UMCG investigates the role of genetic variation in health and the aetiology of autoimmune diseases (e.g. coeliac disease), the role of the gut microbiome therein, and is generating iPSC-based organ-on-chip models to investigate and validate ‘omics’ findings.

The data for these studies are mostly generated by next generation sequencing such as single-cell RNA-seq and ATAC-seq. The generation and analyses of the data requires a broad range of scientific expertise. In our group, a dynamic and highly interactive environment is created in which bioinformaticians, geneticists, statisticians, molecular biologists, stem cell biologists, and immunologists work together closely.

Important findings published by the group are (a) the shared genetics of autoimmune diseases, (b) 95% of the autoimmune disease-associated single nucleotide polymorphisms (SNPs) affect gene expression rather than gene function, (c) eQTL effects of GWAS SNPs on long non-coding RNAs (lncRNAs), and (d) a range of environmental factors affecting the human microbiome.

The current ongoing research is for a large part focused on the prioritisation of SNPs, genes, pathways, and cell types affected in autoimmune diseases, on in vitro experiments to validate the function of the prioritised candidates, and on determining how host genetics affects microbiome composition.

Depending on the background and interests of the student, we will design a working plan for the two-week internship.

Supervisor: prof. dr. Stefan P. Berger, dr. Jaap van den Born

Field of research: Nephrology

Description: In Nephrology Dept. various projects are running using diverse methodologies (see 1- 6). You are invited to express your interests in one of these fields (being either clinical, epidemiological, human- or animal in vivo- or in vitro experimental) to indicate what sub-project interests you most. Please motivate your interest for the specific topic.

1. Patients with renal disease and progressive renal function loss, are being studied with respect to the mechanisms via which the urinary protein leakage results in renal function loss. We aim to modulate proteinuria-driven complement activation on endothelial and tubular cells.

2. Our center also has a large population of renal transplant recipients. These patients are monitored very closely, and regimens aimed at increasing the duration of graft function as well as patient survival are being studied currently. A large database including biobanked urine and plasma is available in TransplantLines. Within this cohort, we try to entangle which factors associate with/contribute to transplant loss and mortality.

3. General population cohorts are studied to detect which parameters lead to initiation of progressive renal function loss and its complications. The cohorts PREVEND and Lifelines from the general population are good examples. The natural course is followed to study possible causes of morbidity and mortality in relation to renal parameters.

4. Lifestyle and the kidney. Many lifestyle factors are involved in the risk of long-term renal function loss. These include smoking as well as nutritional habits, such as excessive caloric intake leading to obesity and diabetes, excessive sodium intake, and a sedentary lifestyle. The mechanisms of renal damage induced by these lifestyle factors are being studied in patients as well as experimental animals, and the effect of lifestyle intervention measures on the course of renal disease is being studied. Nutritional monitoring is part of this project.

5. Endothelial dysfunction highly contributes to progression of renal and cardiovascular diseases. We are interested in the effects of uremic and/or transplantation conditions on the endothelial glycocalyx, and functional consequences of endothelial injury. This work is performed on human (renal) endothelial cells in culture and tissues from renal patients.

6. Immunity and the kidney. Within this research line, we try to unravel the role of the immune system (complement system, leukocytes, endothelial cells) in chronic renal damage in proteinuric and transplanted kidneys. B-cell, endothelial, and complement profiling will be associated with clinical outcome parameters.

Supervisor: prof. dr. Cor Calkhoven

Field of research: ERIBA

Description: Breast cancer is one of the most prevalent cancers worldwide. Breast cancer can be classified into different subtypes requiring different treatments, and despite the existence of treatments for most types of breast cancers, prognosis for metastatic breast cancer is still poor. To develop a more specific and effective
treatment it is crucial to understand the underlying cellular and molecular mechanisms that specify a certain breast cancer subtype.

The transcription factor C/EBPβ-LIP is specifically overexpressed in triple-negative breast cancer and was shown to be involved in cell migration, cancer metabolism, and possibly immune evasion. The student will work on aspects of oncogenic functions of C/EBPβ-LIP. The project will likely involve cell culture, transfection, and immunoblotting techniques as well as assays for cancer cell proliferation and survival.

Optional literature:
Sterken et al. (2022) NPJ Breast Cancer, 8: 11. DOI: 10.1038/s41523-021-00372-z
Ackermann et al (2019) Commun Biol, 2, 1-15 DOI: 10.1038/s42003-019-0461-z

Supervisor: prof. dr. Adriaan A. Voors

Field of research: Cardiology

Description: Heart failure is prevalent worldwide and associated with a high risk of mortality and hospitalization and patients have a poor quality of life. Identifying patients with heart failure with an excessive risk of those clinical events is important to appropriately inform patients and their relatives and to select patients that might
need more aggressive treatment. Some biomarkers (such as NT-proBNP) have a moderate predictive value for clinical outcomes in patients with heart failure. However, we believe that the predictive power of biomarkers could be further improved by studying a much larger number of biomarkers. Recent analytical advances have made it possible to measure a large number of biomarkers from one small blood sample. From 500 patients with heart failure with a reduced ejection fraction (HFrEF) and a preserved ejection fraction (HFpEF) we have measured more than 7000 biomarkers. The student will analyze the strongest biomarkers to predict death and heart failure hospitalization in patients with
HFpEF and HFrEF.

Supervisor: Christian Hulzebos PhD

Field of research: neonatologie

Description: Neonatal jaundice is a condition in which bilirubin levels are elevated, also known as hyperbilirubinemia. Severe hyperbilirubinemia is potentially dangerous, and – when left untreated – may cause permanent brain damage. To prevent the harmless condition of neonatal jaundice from developing into kernicterus, it is highly important to identify the children at risk at an early stage. Jaundice can be identified by visual examination due to its ability to give yellowish color to the skin and sclerae of the eye. However, visual judgement of jaundice severity has proven to be unreliable, even though performed by experienced health personnel. The measurement of bilirubin is traditionally done by blood samples. To reduce the need of drawing blood from the newborn, transcutaneous bilirubinometers have been developed to measure the bilirubin in the newborn skin. Both laboratory equipment and transcutaneous bilirubinometers are rather expensive, with a price of 6-10.000 US dollars, thus making them practically unavailable in low-income countries. Since most deaths due to jaundice occur in low-income countries, there is a large unmet need of simple, reliable and affordable technologies to identify at-risk newborns.  There is a novel instrument that may fulfill these requirements: a smartphone-based application that estimates bilirubin levels based on the color analysis of a digital image.

We hypothesize that the smartphone app in estimating bilirubin levels is highly correlated to transcutaneous or serum bilirubin levels and that this new method is better than the visual estimation of neonatal jaundice. Following our hypothesis, the short-term goal for this project is to assess the user friendliness and hopefully demonstrate the ability of this novel screening method to identify newborns with neonatal jaundice.

Supervisor: Prof. Martin H. de Borst, Drs. Tamas Szili-Torok

Field of research: Internal Medicine, division Nephrology

Description: New onset diabetes after transplantation (NODAT) is an important long-term complication of renal transplantation. It is estimated that up to 50% of renal transplant recipients (RTR) will develop NODAT, which is associated with worse patient and graft outcomes. At the moment, identifying RTR at risk is an unmet clinical need, as reliable biomarkers for early prediction are lacking. However, can a combination of existing clinical biomarkers be used to predict NODAT? In order to answer this question, contemporary machine learning techniques can be used, such as feature selection. Feature selection algorithms select the best combination of non-redundant features that can subsequently be used to build a good performing model. In this project, you will carry out feature selection and you will build a machine learning model using random forest to predict NODAT. Once the model is built, you will use a validation dataset to test the model accuracy.

It is preferable that you have some experience with programming (Python, R, STATA, C, etc.) and that you are familiar with basic statistics and/or basic linear algebra. Previous experience with machine learning or feature selection is an advantage, however, is not a must.

Supervisor: Prof. dr. Riemer HJA Slart, nuclear medicine physician, drs Pieter Nienhuis (MD-PhD student), ir. Gijs van Praagh (BME, PhD-student)

Field of research: Nuclear Medicine & Molecular Imaging and close collaboration with the department of Rheumatology & Immunology.

Description: Giant cell arteritis (GCA) is a large vessel vasculitis most commonly affecting the aorta and its major branches. Within the GCA spectrum, different patterns of vessel involvement may be recognized. In cranial GCA (C-GCA), the arteries of the head and the neck, such as the temporal, maxillary, and vertebral arteries are affected. In large vessel GCA (LV-GCA), arteries such as the aorta and subclavian arteries may be involved. Approximately 70% of patients present with an overlap of these two disease patterns. Nonetheless, C-GCA and LV-GCA differ in their clinical presentation, complications, diagnostic approach, and may also have a different outcome.

Fluorine-18- fluorodeoxyglucose (FDG) positron emission tomography combined with computed tomography (PET/CT) is an imaging test routinely used in GCA patients to detect large artery involvement. Due to their high metabolic activity, inflammatory cells such as macrophages and lymphocytes show high uptake of FDG. The recommended way of analyzing FDG uptake in the arteries is by visual assessment. Additionally, semiquantitative measurements of FDG uptake, such as the standardized uptake value (SUV), are regularly used in research and may offer a more objective measure of inflammation. Assessment of the cranial arteries has historically been difficult due to the high physiological FDG uptake in the brain. Adapting the scanning time (5 instead of 2-3 minutes) of the head improves the quality and may improve the visualization of cranial arteries in patients with CGCA.

The aim of this study is to compare 2 vs 5 minutes PET images of the head visually and semiquantitatively. The student(s) will work with a dedicated software program for analyzing the FDG PET/CT vascular data of the head.

Supervisor: Marianne G. Rots, Ph.D. Professor of Molecular Epigenetics, Luis Alfonso González Molina, Ph.D. Student

Field of research: Pathology and Medical Biology

Description: Mitochondrial dysfunction is the underlying mechanism in neurodegenerative diseases. Recently, mitochondrial DNA (mtDNA) methylation has been proposed to be associated with mitochondrial dysfunction. In our group, we aim to assess epigenetic changes, mainly mitochondrial DNA methylation, associated with the initiation and progression of neurodegenerative diseases. Thus, it is crucial to determine the level of mtDNA methylation accurately and reliably in different in vitro neurodegenerative models. Towards this end, different assays are developed to:
1. purify and characterize mitochondria from various types of cells and tissues.
2. isolate mitochondrial DNA from pure mitochondrial fraction using the Trizol protocol.
3. determine the mtDNA content in the Trizol RNA phase versus the DNA phase/genomic DNA.
4. determine the copy number of mtDNA from pure mitochondria isolated fraction and compare to nuclear fraction.
5. evaluate mtDNA methylation in samples using pyrosequencing and LC-MSMS.

By joining us, the student will learn how to formulate (and design experiments to answer) research questions about the biological role of mtDNA methylation, in the context of neurodegenerative diseases.

Supervisor: Jan-Luuk Hillebrands (PhD, Professor of Experimental Vascular Pathology) and Harry van Goor (PhD, Professor of Experimental Nephropathology). Direct supervisor: Marcelo Cornejo-Alaniz (Msc, Ph.D. student)

Field of research: Vascular Pathology and Experimental Nephropathology

Description:Diabetes mellitus (DM) is characterized by hyperglycemia and can result in alterations in the microvasculature. In pregnancy, Gestational Diabetes Mellitus (GDM) with hyperglycemia can result in altered placental microvasculature that negatively influences fetal and newborn development. In GDM, the formation of
new blood vessels (angiogenesis) in the placenta is increased in response to hyperglycemia. The underlying mechanisms of angiogenesis in GDM are still unknown. Angiogenesis is regulated by several factors, including VEGF, nitric oxide (NO), adenosine, and intracellular pH (pHi). Previous research performed in umbilical vein endothelial cells (HUVECs) showed that in GDM an alkaline pHi due to increased sodium proton exchanger 1 (NHE1) activity, increased NO synthesis, and decreased adenosine uptake is present. Furthermore, increased activity of the transcription factor AP-1 was observed.

The overall aim of this project is to establish the link between AP-1 and pHi in human placental microvascular endothelial cell angiogenesis and how this is altered in GDM. We hypothesize that AP-1 and pHi are critically involved in microvascular angiogenesis in the human placenta in women with GDM. As part of this project, during the 2 weeks IRF you will participate in:

1) the establishment and validation of the placental endothelial cells (hPMEC) isolation protocol from fresh human placenta, and
2) preliminary in vitro experiments to study the possible association between hyperglycemia, AP -1, pHi, and angiogenesis

This IRF project involves preclinical wet lab research using fresh human placenta tissue and in vitro cell culture. Results will increase our understanding of GDM-induced vascular pathology in pregnancy eventually.

Supervisor: Prof. Frans W. Cornelissen. Supervision will be done by a PhD or Postdoc in the group and depend on the specific project.

Field of research: Ophthalmology

Description: In various projects, we use our knowledge about basic vision to come to new methods that can help ophthalmologists and vision rehabilitation workers to better or quicker understand the visual problems of people that come to the clinic.

The project will involve performing, and perhaps even designing, vision tests (responding to images or movies shown on a computer screen) and may also require measuring eye movements.

Supervisors: prof. Hélder A. Santos (Head of Department of Biomedical Engineering)

Field of research: Biomedical Engineering

Description: The recent cutting-edge advances on nanomaterials are anticipated to overcome some of the therapeutic window and clinical applicability of many drug/peptide molecules and can also act as innovative theranostic platforms and tools for the clinic in the future. In the last decade, research on cancer and cardiovascular diseases resulted in a new set of potential treatments with promising results in
the clinics, which culminated with the development of the first nanovaccines for COVID-19. Amongst the different experimental treatments, active cancer immunotherapy, and targeted to the injured heart, hold great promise for the future treatment of these diseases. The students will be introduced to prominent nanosystems, such as biohybrid nanocomposites made of different nanoparticles and cancer cell-based membrane materials as potential platforms for the individualization of medical intervention and biomedical applications. Examples on how biohybrid nanomaterials can be prepared and scaled-up, as well as how they can be used to enhance the drug’s targetability, intracellular drug delivery for both cancer chemo- and immune-therapy applications as well as other applications, will be experienced.

Supervisors: dr. Patrick van Rijn, Clio Siebenmorgen

Field of research: Biomedical Engineering

Description: We employ gas bubbles with antimicrobial crystals encapsulated in these, for the manufacturing or coatings that can deliver antimicrobials using ultrasound. The bubbles are embedded into a slippery/antifouling hydrogel coating that can be visualized externally using medical ultrasound but also by changing the frequency, make them “pop” and thereby deliver the antimicrobial payload. This approach allows on-demand and highly localized delivery with a feed-back loop able to allow for determining whether the bubbles have been popped.