IRF projects 2019

Project A: Pathobiology of lymphoma

Supervisor: Lydia Visser MD PhD

Department: Pathology and Medical Biology

Project introduction: Research in the pathogenesis of several types of lymphoma, as well as new targets for treatments can be performed. Our research group exists of pathologists, molecular biologists, haematologists and immunologists. The exact subject will be decided on at the last moment, depending on the interest of the student, if possible. What is an intriguing question we are working on at the moment and what is possible in the limited time.

Project B: Repair of kidneys with normothermic machine perfusion before transplantation

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

Department: Surgery

Project introduction: 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

Project C: Food ingredients and immunity

Supervisor: Prof. Paul de Vos PhD

Department: Pathology and Medical Biology

Project introduction: During recent year it has been shown that food ingredients are not only important for nutrition but also for keeping our immune system active. Many food ingredients such as dietary fibers are consumed by the 100 trillion bacteria in the intestine and form immune active components such as short fatty acids. This fine-tunes  immune responses against pathogens. Also some food components can directly interact with the immune system. In this project you will be involved in testing food ingredients that might be instrumental in enhancing responses against pathogens or reduce the chance on ageing associated diseases.

Project D: Nephrology

Supervisor: Martin de Borst MD PhD, Jaap van den Born MD PhD

Department: Internal Medicine, Division of Nephrology

Project introduction: In Nephrology Department 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.

  • 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. Both non-diabetic- and diabetic renal disease are studied. Most of these patients are included in clinical trials to study the efficacy of regimens to lower proteinuria and to prevent progressive renal function loss.
  • 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.
  • 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.
  • 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 excess caloric intake leading to obesity and diabetes, excess sodium intake and 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.
  • Various animal (rat) models of proteinuria and progressive renal disease are being studied, in order to unravel the mechanisms of renal damage and to optimise antiproteinuric and renoprotective treatments. Focus points are the RAAS – Vitamin D – FGF23 axis; progression of structural tubulo-interstitial changes; and the interplay of proteinuria and dyslipidaemia.
  • Innate immunity and the kidney. Within this research line we try to unravel the role of innate immune system (complement system, leukocytes, chemokines) in chronic renal damage in proteinuric and transplanted kidneys. By intervention of novel heparin(oid) related drugs we aim to reduce the contribution of inflammation in chronic renal tissue remodelling. Research is largely done in vitro and in experimental models of renal disease.

Project E: Systems genetics of immune-mediated diseases

Supervisor: Sebo Withoff MD

Department: Genetics     

Project introduction: The Immunogenetics group of prof. Cisca Wijmenga PhD (Department of Genetics of the UMCG) investigates the role of genetic variation in the aetiology of autoimmune diseases (e.g. celiac disease, inflammatory bowel disease and multiple sclerosis) and the role of the gut microbiome in health and disease.

The data used for these studies are mostly generated by next generation sequencing. The generation of the data and the analyses requires a broad range of scientific expertise. In her group, a dynamic and highly interactive environment is created in which bioinformaticians, geneticists, statisticians, molecular biologists and immunologists work together closely.

Important findings published by professor Wijmenga 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), (d) the enrichment of ‘lymphocyte specific’ long intergenic non-coding RNAs (lincRNAs) in celiac disease associated loci, and 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 (with currently a strong interest in the mechanisms of lncRNAs) and on determining how host genetics affects microbiome composition.

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

Project F: Personalized medicine in patients with diabetes and tuberculosis

Supervisors: Job van Boven MD, Jasper Stevens MD

Department: Pharmacology

Project introduction: The department of Clinical Pharmacy & Pharmacology of the UMCG performs preclinical, translational, and clinical research. Research is focused on personalised medicine and targeted pharmacological therapy, mostly applied to diabetes mellitus type 2 (and its cardiovascular and nephropathic complications) and infectious diseases (tuberculosis [TB], HIV).

Topics within personalised medicine include optimisation of pharmacotherapy (individual response variability, therapeutic drug monitoring, pharmacogenetics, biomarkers, molecular imaging), conducting large clinical trials with investigational medicinal products, drug utilisation research (real-world outcomes such as medication adherence, safety and cost-effectiveness) and development and regulatory assessment of new drugs and dosage forms.

We offer the IRF project that will focus on drug-related issues in patients with diabetes mellitus type 2 and/or tuberculosis. Are TB drugs clinical effects affected by co-existing diabetes? Do the current TB and diabetes drug trials reflect real-world patient’s characteristics? What is needed for personalised medicine in TB and diabetes treatment? What can we do to optimise adherence to treatment? To assess these issues, you can make use of our in-house database (GIANTT, www.giantt.nl) with anonymised patient records of over 20,000 patients with diabetes type 2, TB drug data and learn from our experienced multidisciplinary team of physicians, pharmacists, and clinical researchers.

For questions regarding this project, please contact: dr. J.F.M. van Boven, assistant professor of Drug Utilization Research (j.f.m.van.boven@umcg.nl)

Project G: Development of an instrument to measure the functionality of people with prosthetic hands

Supervisor: Paul F.M. Krabbe PhD, Karin M. Vermeulen PhD

Department: Epidemiology

Project introduction: A prosthesis is an artificial device that replaces a missing body part, which may be lost through trauma, disease, or congenital conditions. Prosthetics are intended to restore the normal functions of the missing body part. Prosthetic amputee rehabilitation is primarily coordinated by a prosthetist and an interdisciplinary team of health care professionals including psychiatrists, surgeons, physical therapists, and occupational therapists. A person’s prosthesis should be designed and assembled according to the person’s appearance and functional needs. Different types of prosthesis exist, and it is not clear what type is most effective.

Health-status or health-related quality of life instruments are necessary tools to evaluate health outcomes in patients. Available instruments in the field of hand prosthesis are domain specific, lengthy, and developed from the experts’ perspective. Yet, there is nopatient-centred instrument that evaluates the perceived health status of hand prosthesis patients. We aim to develop a patient-centred compact (short) and attractive instrument that can be used to evaluate the health status or functional status in patients with a hand prosthesis.

In this project students will first understand what patient-centred health status is and how it can be measured. Then, we will look for health items that are essential to choose for our planned instrument. Next, students will develop a graphical representation of the health items (HealthFan) and formulate a strategy to select the most relevant health items among the generated set of candidate items. Finally, the students construct a prototype of the Hand Prosthetic instrument (HealthSnApp).

Project H: Next generation sequencing: first diagnostic one-stop show in clinical microbiology and infection prevention

Supervisor: Prof. John Rossen MD PhD

Department: Genomics

Project introduction: Our research group “Personalised Microbiology” that is closely linked to prof. Alex Friedrich MD PhD’s research group “Genomics of Infection Prevention” has successfully implemented the use of next generation sequencing for routine clinical microbiology and infection prevention. The method is used to determine the genetic relationship between pathogens (used to guide infection prevention measures) and for the molecular detection and further characterisation of (emerging) pathogens. This includes analyses for revealing (new) antibiotic resistance mechanisms and for determining the virulence of pathogens resulting in improved risk assessment and infection prevention. In addition, based on comparing whole genomes of bacteria, tailor-made diagnostic tests are developed used for specific detection of outbreak and/or virulent bacterial strains.

Nowadays we apply the method in several projects dealing with the above-mentioned topics. Our projects are not only focused on patient samples but also to animal-, food- and water samples. Apart from characterising the micro-organisms (including viruses) the interaction between them as well as with their host is studied.

The student will be able to participate within one of the running projects depending on his or her interests as well as on the possibilities available in June 2019.

Project I: Epidemiology and pathophysiology of heart failure

Supervisor: Prof. Adriaan A. Voors MD PhD

Department: Cardiology

Project introduction: Heart Failure is a syndrome defined as typical symptoms (such as dyspnoea and/or impaired exercise tolerance) caused by a functional or structural cardiac abnormality. It is one of the fastest growing epidemics with a poor quality of life and a very high morbidity and mortality.  The department of cardiology is a world leader in research in the epidemiology and pathophysiology of heart failure.

During a two-week fellowship, the candidate can experience current projects that we are running on the use of omics (genomics, transcriptomics and proteomics) to gain a better insight in the pathophysiology of several specific phenotypes of heart failure.

Project J: Big data and deep learning in cardiology

Supervisor: Prof. Pim van der Harst MD PhD, Hilde Groot, Jan-Walter Benjamins

Department: Cardiology

Project introduction: The department of Cardiology of the University Medical Center Groningen (UMCG) performs preclinical, translational, and clinical research. One topic of interest is focused on understanding complex associations among molecular, clinical, and imaging data to enhance our understanding of the development and progression of cardiovascular disease. The electrocardiogram, molecular data and imaging data of large datasets are analysed by novel machine learning techniques to progress this field.

We are looking for students that are enthusiastic about applying deep learning techniques to create new ways for analysing big data sets of electrocardiographic, imaging, genetics, and biomarker data. You will need to become comfortable with some programming, as it touches the area of computational biology and computer science. In this project you will learn about ECG/imaging-patterns and learn how to create deep learning algorithms to recognize these patterns. These algorithms may then be used to uncover new biological pathways and to better understand the pathophysiology of cardiovascular disease.

Project K: Regulation of hematopoietic stem cells

Supervisor: Prof. Gerald de Haan MD PhD

Department: European Institute for the Biology of Ageing (ERIBA)

Project introduction: The group is interested in a unique genetic and epigenetic programme that distinguishes stem cells from non-stem cells. The research group of Prof. de Haan uses state-of-the art genomic tools to search for common molecular events in stem cells at distinct phases in hematopoietic development and aging. The team studies how stem cells can be transplanted, and which mechanisms ensure their proper homing and subsequent engraftment to the bone marrow after transplantation. Stem cells are defined by their ability to self-renew and their ability to differentiate into all lineages within a tissue. The group is addressing how stem cell self-renewal alters with age, and how enhance stem cell renewal can be exploited in stem cell expansion protocols in vivo and in vitro.

Please check our website for more information: (http://eriba.umcg.nl/groups/ageing-biology-and-stem-cells/)

Project L: Current systems of left and right ventricle unloading during extra-corporeal life support.

Supervisor: Prof. Massimo Mariani MD PhD

Department: Cardio-thoracic surgery

Project introduction: Patients necessitating an extracorporeal (ECLS) life support, either in the form of veno-arterial (ECLS) or in the form of an isolated left ventricular (ECLS) support, experience often left or right ventricular overloading. To prevent this problem the student will provide an overview of the existing right and left ventricular temporary unloading systems. The student will be attending clinical cases of ECLS in the UMCG, if they are available during the two week IRF-period.

Project M: Chromosomal instability in cancer and ageing

Supervisor: Floris Foijer MD PhD

Department: European Research Institute for the Biology of Ageing (ERIBA), UMCG

Project introduction:                   

In each cell division, our complete genome is replicated and segregated equally over the two emerging daughter cells. Cancer cells have an intrinsic tendency to mis-segregate chromosomes occasionally, a process known as chromosomal instability or CIN. CIN results in cells with an abnormal chromosomal content, a state defined as aneuploid. Indeed, more than two out of three cancers are aneuploid, suggesting that CIN somehow contributes to the transition of normal cells into cancer cells.

Paradoxically, CIN and the resulting aneuploidy pose a growth disadvantage to non-cancer cells, suggesting that cancer cells have found ways to cope with the detrimental consequences of aneuploidy. In our lab, we try to map and understand how aneuploid cells transform into aneuploid cancer cells. We developed state of the art mouse models, in which we can provoke CIN in tissues of choice at time points of choice. Using these models, we have shown that whereas CIN is indeed detrimental for some stem cells, it is remarkably well tolerated by epidermal cells, although aneuploid mouse epidermis appears prematurely aged (Foijer et al, PNAS 2013). Furthermore, we found that CIN alone is not sufficient for cancer, but that predisposing mutations (such as p53 inactivation) are required for aneuploidy to contribute to malignancy (Foijer et al, PNAS 2014; Foijer et al, eLife 2017). The main aim of the lab is to develop new intervention strategies that can selectively kill aneuploid cells. For this, we need to better understand the biology of aneuploid cells and which (epi)genetic alterations are required to transform aneuploid cells into their malignant counterpart.

In this IRF project, you will be introduced into  the exciting field of chromosome biology. This includes time lapse microscopy, cytogenetics, mouse models, pre-clinical intervention, and state of the art technology such as single cell sequencing (see Bakker et al, Genome Biology 2016) and RNA sequencing. While 2 weeks will not be sufficient to finish a full project, your IRF stay will reveal how we try to fulfil our mission to identify aneuploidy-killing compounds and we will involve you the experiments that are ongoing at that moment in time. More importantly, you will also learn whether the field of chromosomal instability is a field for you to pursue in your future research avenues. Looking forward to seeing you in June!

Project N: Bronchoscopic lung volume reduction for patients with severe emphysema

Supervisor: Dirk-Jan Slebos MD

Department: Groningen Research Institute of Asthma and COPD

Project introduction: Bronchoscopic lung volume reduction (BLVR) is a last resource treatment option for patients with severe emphysema. Options include both valves and coils. These treatments reduce hyperinflation, alleviating lung mechanics, resulting in less dyspnoea. However, little is known on the effects of BLVR on lung compliance and airway resistance.

In this project we want to evaluate the effect of BLVR on changes in airway resistance using resistance/volume changes, and the differences on these outcomes for valves and coils.

The way we want to evaluate this effect is through retrospective data analysis, literature review and we will be attending actual BLVR procedures.

Project O: Depression and cognition in later life: one size fits all?

Supervisor: Marij Zuidersma MD

Department: Psychiatry

Project introduction: Interventions according to a standardized protocol will hardly, or never, be effective for all or the majority of patients. As a consequence, it is increasingly being recognized that patient care needs to be individualized, both in general medical health care as well as mental health care settings. In contrast to this increasing thrive for more individualized patient care, the majority of studies still have a nomothetic design. That is, nomothetic studies calculate group-average estimates, thus yielding knowledge on “what is true on average”. Although nomothetic studies can be useful if one wants to make inferences about the average tendency, prevalence or risk in the population, their results will not generalize to individual patients, which might be an obstacle in developing more personalized interventions.

An alternative to the nomothetic study is the single-subject study. Instead of comparing individuals with each other, in single-subject studies individuals are compared with themselves. By using multiple assessments within one individual, an individual serves as his or her own control. In these 2 weeks you will learn more about when and why to use a single-subject study. We have time-series data of 10 older persons with depression and cognitive impairments, comprising 63 daily assessments of sleep, depression, cognitive functioning, physical activity and several other variables. You will get the opportunity to evaluate for one or all of these persons the temporal relation amongst these variables, and will compare your results to what is known from previous studies that used a group-based approach.

Project P: The effects of age, muscle size, muscle architecture, and walking environment on the variability walking patterns

Supervisor: Claudine J.C. Lamoth MD

Department: BCN-BRAIN Human Movement Sciences

Project introduction: Walking is an important form of daily physical activity. More than 60% of all elderly aged 80 years or older have walking or balance disorders.  Impairments in walking may have several important health-related consequences. Walking impairments may reduce physical activity with serious implications for mobility, fall risk, healthcare use and mortality. Also walking impairments reduce the quality of life. Walking can thus be considered as an important predictor for health status especially in older adults.

Also, healthy aging is associated with changes in walking and mobility. Changes in walking with ageing include a slower walking speed, a decrease in stability, smoothness and complexity of the walking pattern. Underlying mechanism of these age-related changes in the walking pattern are unclear. An important change with advancing age is the reduction of muscle size, called sarcopenia. We hypothesize that age related changes in muscle mass, will contribute to the changes seen in the walking pattern of older adults. However, until now this has not been examined in previous studies. Therefore, the purpose of the project is to determine how muscle size and age are related changes in walking patterns.

In this project the walking pattern of 15 healthy young and 15 healthy older adults will be assessed. Properties of lower leg muscles in this study will be quantified using ultrasound measurements. Changes in the walking pattern will be examined using Inertial Measurement Units (sensors that record accelerations of the movement). Thee walking pattern will be measured both in natural (inside/outside) and laboratory environments (treadmill walking).

Contribution / activities of fellow: 

Under supervision of the PI (Claudine lamoth) and a PhD student (Iris Hagoort) you will assist with the measurements, contribute to a literature review, and can perform a part of the data-analysis according to your specific interest.

You will participate in weekly lab meetings involving students of all levels (Bachelor, Master, PhD) and 2-weekly Healthy Ageing research meetings with staff, Master and PhD students.

Project Q: Stem cell therapy to treat radiation-induced side effects

Supervisor: Prof. Rob P. Coppes MD PhD

Department: Cell Biology and Radiation Oncology

Project introduction: Xerostomia (dry mouth syndrome) can be caused by dysfunctional salivary glands (SG) due to aging, radiotherapy for head and neck tumours and the auto-immune diseases such as Sjögrens syndrome. About 25% of the elderly and 40% of the patients treated for head and neck cancer suffer from oral dryness leading to impaired speech, chewing, taste and swallowing, higher susceptibility for infections, and caries. These sequelea severely affect the patients’ wellbeing and quality of life. A lack of viable stem cells able to maintain glandular homeostasis underlies age and radiotherapy induced SG dysfunction. Therefore, stem cell therapy could ameliorate xerostomia. Indeed, recently we showed that transplantation of mouse or human SG stem cells can rescue murine SG from radiation damage. For patients receiving radiotherapy, collection of stem cells before cancer treatment seems feasible. However, the definitive salivary gland stem cell has not been characterized yet. This project will attempt to understand the mechanisms behind stem cell maintenance and differentiation, to allow stem cell therapy in the future.

Project set-up

The student will participate in the culturing and testing of salivary gland stem cells in vitro. Primary cells are obtained from mouse or human salivary glands and cultured as salispheres.  Dispersed single cells selected with FACS for the expression of stem cell markers are passaged to Matrigel to form secondary spheres and organoids. The expression of genes and stem cell markers involved in the stemness of these cells are investigated. Involved signalling pathway will be manipulated to assess their role in stem cell maintenance, expansion and differentiation.

Project R: Understanding the pathophysiology of SHOCK-mediated organ failure in order to improve the clinical care of critically-ill patients

Supervisor: Dr. J. Moser

Department: Critical Care

Project introduction: Every day, critically ill patients in ICUs worldwide develop failure of vital organs usually as a result of infection (sepsis) or injury (trauma or surgery). This so-called multiple organ dysfunction syndrome (MODS) leads to increased mortality among ICU patients. If patients survive MODS, their increased morbidity persists long after they have left the ICU. The incidence of sepsis is increasing worldwide mainly due to the ageing population, often burdened by multiple comorbidities, as well as the growing problem of antibiotic resistance. Unfortunately, there is currently no effective treatment beyond organ support emphasizing the urgent need for a better understanding of the pathophysiological and molecular mechanisms in order to identify new therapeutic approaches.

One of the failing organs in septic patients is the kidney. If patients survive, they have an increased risk of developing chronic kidney disease (CKD) and/or end stage renal disease (ESRD) which can result in dialysis dependency. The underlying mechanisms of sepsis-associated acute kidney injury are still unknown. However, one of the major pathophysiological consequences is loss of microvascular integrity and exaggerated microvascular inflammation. Current research projects focus on understanding aberrant microvascular integrity and inflammation. For these studies, a variety of experimental techniques including immunostaining, western blotting, RT-qPCR and ELISA are used to analyze in vitro cell studies, kidney tissue from in vivo sepsis models and patient material. For more info: https://www.ebvdt.nl/shock-research

Project S: Gene regulation in ageing and age-related diseases

Supervisor: Prof. Cornelis F. Calkhoven PhD

Department: Biology of Ageing – ERIBA

Ageing, metabolic disorders, and cancer share common biological mechanisms. Cellular factors that are involved in sensing nutrient (food) and energy availability are decisively involved in ageing and lifespan determination, as well as in the development of age-related diseases like cancer or metabolic diseases. The primary research focus of the Calkhoven lab is determining how metabolic and other growth signals control the expression of specific sets of genes that can alter the organism’s normal function or contribute to disease.

Currently, the Calkhoven lab studies a specific pathway (mTORC1-pathway) that senses if enough nutrients and energy are available to regulate cell growth through the control of protein synthesis and/or other metabolic processes. The Calkhoven lab is particularly interested in the function of mRNA control elements, protein factors and microRNAs that are involved in mTORC1-controlled processes. Using mouse models they examine the function of these elements, and other factors, on organismal health and life span determination. In addition, they study the modification of gene regulatory proteins by cellular metabolites and how this regulates cell function under different nutritional conditions. With the aim of ‘translating’ the fundamental research into clinical-pharmacological applications, the lab is also involved in developing reporter systems for potential compound screening strategies.

Project T: Liver transplantation

Supervisor: Aad van den Berg MD

Department: Gastrointestinal medicine

Project introduction:

During the research period one of the following research subjects will be adressed:

  1. Is muscle strength a prognostic factor for survival after liver transplantation? It has been shown that low muscle mass as assessed by CT scanning is associated with worse survival in patients on the waiting list for liver transplantation, and with inferior peri-transplant survival. We also have shown that creatinine excretion in 24H urine (reflecting muscle mass) as measured one year after liver  transplantation is a strong, independent predictor of subsequent survival during the next 15 years. It is not known whether 24H creatinine excretion in these patients (i) truly reflects muscle mass, (ii) predicts survival, and if so, (iii) which factors (e.g., type of immunosuppressive regimen, original  liver disease, metabolic complications) determines muscle strength in these patients.  We collected a dataset of >500 measurements of muscle strength and creatinine excretion in >300 liver transplant recipients. This database will be used to answer these questions.
  1. “Minimal” immunosuppression in ultra-long survivors after liver transplantation. Patients surviving the first year after liver transplantation (>90% in our center) have a 50% chance of being alive at 20 years after transplantation. Relatively little is known about the use of immunosuppressant drugs these extremely long-term survivors. Rejection seldomly occurs in them, suggesting that a state of near-tolerance has been achieved. This study is intended to describe in detail the use of immunosuppressive drug in this population and to investigate whether low-level immunosuppression is associated with a low incidence of immunosuppression-related side-effects (infections, cardiovascular disease, cancer, renal dysfunction).
  1. Long-term effects of calcineurin-inhibitors on renal function after liver transplantation. It is well-known that calcineurin-inhibitor may have deleterious effects on renal function. Careful dosing, keeping drug levels low, is considered by many to be relatively safe at least during the first years after transplantation. However, liver transplant patients may a expect very long survival (>20 years), and information about long-term renal toxicity is scarcely available. We want to study this by comparing kidney function in ultra-long surviving patients who have been treated with the calicineurin inhibitors Ciclosporin A or Tacrolimus with that of patients who never used these drugs, or only for a limited number of years.
  1. Is the liver truly an immune-privileged organ? It is often stated that the liver is “different”  from all other solid organs because only low amounts of immunosuppressive drugs are necessary to prevent rejection. However, good evidence for this statement is lacking. It could well be that the liver can tolerate low-grade rejection (due to relative under-immunosuppression) much better than other organs (e.g., kidney or lungs) because the liver has a much greater capacity for regeneration than these other organs. We want to study this hypothesis by comparing liver tests in liver transplant patients (receiving a typical liver transplant immunosuppressive regimen) and in patients who have received a liver plus kidney, pancreas or lung(s) (who receive the more intense immunosuppressive regimens of those other organs).

Project U: What is the role of hypoxia in non-alcoholic fatty liver disease?

Supervisor: Prof. Han Moshage MD PhD

Department: Hepatology

Project introduction: Non-alcoholic fatty liver disease (NAFLD) is a common condition characterized by fat accumulation in liver cells (steatosis), which may evolve to an inflammatory and fibrotic condition named non-alcoholic steatohepatitis (NASH). Transition from steatosis to NASH is not fully understood, but extracellullar vesicles (EV’s) seem to play an important role. Recent clinical observations made in patients with syndrome of obstructive sleep apnea (OSA), suggest that hypoxia may contribute to disease progression through induction of the transcription factor hypoxia inducible factor 1α (HIF-1α). Our research question is whether hypoxia modulates the release of EV’s released from steatotic hepatocytes and its role in the transition from steatosis to NASH.

Project V: LifelinesNEXT - Introduction to scientific challenges in broad phenotyped cohorts

Supervisor: Prof. Sicco Scherjon MD PhD

Department: LifelinesNEXT

Project introduction: LifelinesNEXT is a prospective birth cohort of mothers, fathers and babies, which includes extensive sample collection starting at 12 weeks of gestational age until at least the age of one year. A variety of biomaterials is collected including blood, stool and breastmilk at multiple time points. Data on environmental, social and medical factors are collected via questionnaires at 14 time points. LifelinesNEXT offers an opportunity to relate integrated information on microbiome, metabolism, immunology, genetics, epigenetics and environmental influences. The LifelinesNEXT cohort will consist of ~1500 pregnant mothers, their new-borns and partners. In this project we will introduce the student to the many scientific opportunities that occur in a broad phenotyped cohort and LifelinesNEXT in particular.

During the 2 weeks project students will get acquainted with the ongoing process of including pregnant women, the extensive data collection on mother and child, the preparation of biosamples and the first data analysis.

The course will cover three aspects of research in birth cohorts:

  1. Bio sample collection
    Students will accompany a research nurse during their home visits to participants. Participating in the elaborate research project LLNEXT requires a lot of effort from the participants. Therefore NEXT gives ample attention to the warm contact with participants and visits them at least 4 times.
  2. Lab introduction

All kinds of biomaterials collected in NEXT (breastmilk, blood and stool) are processed and prepared for genotyping at the laboratories of the Genetics department UMCG. By participating in this process, students will be introduced in the fascinating world of genetics.

  1. Data analysis

The first data from questionnaires became available recently. Our students will perform data analysis to give insight in the inclusion process and provide a first characterisation of NEXT participants. The students will prepare a report on several topics, e.g. food intake of included newborns and characteristics of exclusively breastfed babies.

Project W: Genetic epidemiology & genome-wide association

Supervisor: Peter van der Most, PhD

Department: Epidemiology

Project introduction: Genetic epidemiology is the study of the distribution of genetic traits across the population, and their influence on health and disease. One of the cornerstones of genetic epidemiological research is the Genome-Wide Association Study (GWAS), a method to find genetic variants associated with a specific phenotype, such as heart rate, kidney disease, or even education level. In the past two decades, thousands of phenotypes have been investigated by GWAS.

However, how meaningful are such population-based results for a single person? In this project, we will look at an individual genome, and test what these studies predict about the individual’s phenotype.

Alternatively, we will investigate the results of a meta-analysis of GWAS. A GWAS tells us which genetic variants are associated with a phenotype, but not how. Sometimes a GWAS hit is found in a clearly associated gene (for example: a GWAS of blood pressure finds a hit in a gene associated with kidney function), but frequently this is not the case. And even if it is, it does not tell us how this variant affects the phenotype. The follow-up of GWAS is therefor an increasingly important part of genetic epidemiology. We are currently working on a GWAS of end-stage renal disease; if the results are ready in time, the student can chose this as his project.

The project will be entirely computer-based; using the software and methods applied by genetic epidemiologists. No previous experience is required, though some facility with computers will be needed.

Project X: Genome instability influencing protein quality control

Supervisor: Steven Bergink MD PhD

Department: Biomedical Sciences of Cells and Systems

Project introduction: Our proteomes are maintained by the cellular protein quality control pathways that include both molecular chaperones and the cellular degradation machineries. This maintenance is necessary for nascent chains (the newly born polypeptides) but also to deal with other forms of proteotoxic stress that arise due to internal or external stimuli. Alteration of the genetic code will impact the proteome and may in fact cause proteotoxic stress as wel. However, how somatic mutations affect our proteomes and which cellular pathways are dealing with this presumed link is currently unclear. Currently we are investigating this link in more detail and this will be the focus of this project.

Project Y: Recharging the heart: can we harness the power of ketones

Supervisor: Daan Westenbrink MD

Department: Cardiology and Thorax Surgery

Project introduction:

Heart Failure (HF) remains a devastating disease that is characterized with severe symptoms, frequent hospital admissions and a grim prognosis. New strategies to treat or prevent HF are therefore urgently needed.

In HF patients, the cardiac capacity to oxidize fats and sugars is severely diminished, making the heart resembles an “engine out of fuel”. This causes exercise intolerance, which is one of the earliest and most debilitating consequences of HF and often used to diagnose HF.

Ketones function as a cardiac super fuel and are used by athletes to boost exercise performance. We believe that they may also be beneficial for HF patients. We are currently testing if a simple sports drink containing ketones or drugs that stimulate ketone production can improve exercise performance in HF patients. To test this we use advanced magnetic resonance spectroscopy which allows us to detect ATP-production during exercise.