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.