ISCOMS Research Fellowships projects 2018
Project A: Chromosomal instability in cancer and ageing
Supervisor: Floris Foijer PhD
Department: European Research Institute for the Biology of Ageing (ERIBA), UMCG
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 exposed to 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 (also 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 see you in Summer!
Project B: Epigenetic programming of adult disease
Supervisor: Torsten Plösch PhD
Department: Obstetrics and Gynaecology
Our research is focused on the influence of the early fetal and neonatal environment on the health of the offspring at adult age. Specifically, we study how disturbances in maternal-fetal nutrient supply during pregnancy and early postnatal nutrition influence later metabolic regulation. The key idea is that nutrients or other biologically active molecules induce epigenetic changes in the placenta, embryo, fetus or newborn that persist into adulthood and hence change the susceptibility to develop chronic disease (metabolic programming, epigenetic programming).
Our projects therefore focus on several aspects of early development: in material from early human pregnancy we aim to identify epigenetic changes preceding developmental complications. On the other hand, we study how maternal diabetes, maternal lifestyle or pregnancy complications such as preeclampsia can lead to epigenetic modifications in the placenta or the offspring.
Our work forms a bridge from fetal physiology via epigenetics to long-term health outcome. The students will get the opportunity to work on epigenetic mechanisms in cell systems or samples obtained from animal or human studies.
Project C: Molecular eating: feed your microbes to support immunity
Supervisor: Prof. Paul de Vos PhD
Department: Pathology and Medical Biology
The human gut harbours trillions of microbes. Current estimates are that the human gut harbours a tenfold more microbes than human cells and contains 150 times more genes than the human genome. The recent change of the traditional view that gut microbiota effects are not only limited to fermentation of food components but also influence immune status has led to the realisation that these microbes can impact health on different levels and are instrumental for maintaining health. During recent years, it has been demonstrated that microbes in the intestine can easily be influenced by external factors such as diet and antibiotics which may disturb the microbiota-host interactions in an undesirable way and can ultimately lead to disease. An imbalance in microbiota communities in the intestine is implicated in a large number of Western diseases. This correlates with lowering of dietary fibers in Western diets. We found evidence that beneficial effects of dietary fibers are highly dependent on its chemical structure. Some structures serve as food for the microbiota and support production of degradation products with beneficial effects on the immune system. Other chemical structures however, bind directly to sensors on immune cells and support or regulate immune processes directly. Unravelling the mechanisms on how molecular components in our food stimulate immune regulation can lead to prevention and treatment of disease.
Research question/problem definition:
A specific carbohydrate contributing to improved immunity is pectin. In the present proposal, we will investigate how molecular variations in the molecule will contribute to improved immune responses by binding to specific pattern recognition receptors or by serving as microbiota consumable carbohydrate and prevent undesired inflammatory responses. The efficacy will be tested in animal models with specific disorders in different parts of the gastrointestinal tract.
Project D: Signaling in time and space matter: towards personalized medicine with “old” second messengers
Supervisor: Prof. Martina Schmidt PhD
Department: Molecular Pharmacology/GRIP
The human genome encodes as the largest family of receptor proteins the G protein-coupled receptors (GPCR’s), which represent the largest group of drug targets. The concept of agonist bias at GPCR’s has transformed our understanding of cellular regulation by providing the ”old” second messenger concept and, importantly, the conceptual roots of compartmentalised signalling. Key players in compartmentalised GPCR signalling networks are cyclic nucleotide cyclases, that synthesise cAMP and cGMP, phosphodiesterases, that hydrolyse cyclic nucleotides, and scaffolding proteins of the A-kinase anchoring protein family next to protein kinase A (PKA), and the exchange protein directly activated by cAMP (Epac). Adaptation of GPCR signalling bias likely address several preclinical challenges of modern drug discovery. Spatiotemporal dynamics in the subcellular distribution of GPCR signalling networks likely determine the net outcome of several detrimental processes, including chronic inflammation or altered metabolism. Such networks funnel into mitochondria, the key organelles of energy metabolism. Preservation of mitochondrial function is essential in maintaining cell survival and increase longevity, and most importantly, keep key players of GPCR signalling in the right place in the right time. The concepts of signal bias, signal compartments and mitochondrial stress will be merged on the level of GPCRs.
Special focus will be on the novel molecular mechanisms preserving cellular GPCR compartments and mitochondrial functions to alleviate symptoms of chronic inflammation as origin of diseases as heart failure, pulmonary hypertension, asthma, COPD, (cystic) fibrosis, Parkinson, Alzheimer’s disease, and microbial infections. We focus on mammalian cells, tissue cultures and animal models as necessary tools for gaining an understanding of the molecular pharmacology of a drug. Though in vitro drug screening is well established, it is often difficult to accurately extrapolate test results back to possible therapeutic or pathological effects in the human being. As a result, a large majority of drug candidates fail in clinical trials. Using microfluidics, precision-cut-tissue slices, we intend to create microenvironments that better mimic the in vivo situation.
Project E: Nephrology
- Jaap van den Born MD PhD
- Martin de Borst MD PhD
Department: Department of Internal Medicine, Division of Nephrology.
In the 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 major focus point is on the involvement of viral infections in chronic renal transplant dysfunction.
- 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 optimize antiproteinuric and Reno protective treatments. Focus points are the RAAS – Vitamin D – FGF23 axis; progression of structural tubule-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 the 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 experimental models of renal disease.
Project F: The pathophysiology of Heart Failure
Supervisor: prof. Adriaan A. Voors MD PhD
With 5 million patients in the US, and 10 million patients in Europe, heart failure is one of the most common diseases in the world. Every year, more than 3 million heart failure hospitalizations occur in these regions. When a patient is admitted for acute heart failure, the risk of dying or the need for re-hospitalization within 6 months exceeds 30%. Therefore, heart failure is a very prevalent clinical syndrome with high morbidity and mortality. In our department, we aim to better understand the underlying mechanisms of this disease, hopefully leading to better and more targeted treatments of these patients. Therefore, the main study aim of our department is:
“To use genetics, epigenetics, proteomics, and biomarkers to better understand the pathophysiology of heart failure, in order to improve and personalize treatment, leading to better outcomes.’’
To obtain these goals, our main research topics are:
– To study the interaction between cardiac and renal disease in heart failure, the so-called cardiorenal interaction
– To study the value of biomarkers in heart failure for better understanding of the disease, to improve diagnosis and prognosis, and to guide therapy of patients with heart failure
– To study the interaction between genetics, epi-genetics, proteomics, and existing biomarkers to detect pathways of disease in subgroups of patients with heart failure, with the aim to find better individualized treatments for patients with heart failure.
– To study co-morbidities that often accompany heart failure, and to find underlying disease mechanisms.
Project G: Gene regulation in ageing and age-related diseases
Supervisor: Cornelis F. Calkhoven PhD
Department: European Institute for the Biology of Ageing (ERIBA), University Medical Center Groningen (UMCG)
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 H: Nuclear Medicine
Supervisor: Walter Noordzij MD
Department: Department of Nuclear Medicine
Nuclear medicine is a field that uses radioactivity for imaging and therapy. The radioactive molecules are attached to substances that are used in all kinds of body processes. For example, a glucose analogue is used to visualise high metabolic processes, such as primary tumours and their metastases. The effective radioactive dose to the patient is very low, due to the low amount of radioactivity and short half-life of the isotopes.
In this research programme you will investigate the role of this glucose analogue (fluorine-18 labelled fluorodesoxyglucose, or FDG) in staging patients with melanoma. Up to now, all patients undergo total body scanning, i.e. from the top of the skull until the toes. However, in patients with a primary tumour located above the groin, scanning from the top of the skull to the mid-thigh is maybe sufficient. The consequent reduction in scanning time is potentially beneficial for both the patient and the department’s logistics.
You will analyse scans of melanoma patients regarding the site of the primary tumour, and the location of the metastases. You should be able to answer the question to what amount a reduction in scanning time would have consequences in staging the patients. So, will we under stage some patients? Will that have consequences for therapeutic options?
Project I: Immunogenetics of Autoimmune Diseases
Supervisor: Dr. Sebo Withoff
Department: Department of Genetics
The Immunogenetics group of professor Cisca Wijmenga (chair of the 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 on 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 prof. 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 try to design a working plan for the two-week internship.
Project J: Cardiothoracic surgery
Department: Cardiothoracic Surgery University Medical Center Groningen (UMCG).
Supervisor: Prof. M. Mariani MD PhD
The Cardiothoracic Surgery is part of the Thoracic Center of the University Medical Center Groningen, which consist of a Cardiology department and department of Cardiothoracic Surgery. The Cardiothoracic department has a total of 94 beds, and four surgical operating rooms. On an annual basis the department performs ca. 1.700 surgical interventions. The department participates in several clinical and research projects among other in Transplantation/Organ preservation (Heart, Lung and Heart-Lung transplantations), Aortic Surgery, Aortic and Mitral valve sparing surgery, Atrial Fibrillation, Minimal Invasive Surgery and off-pump coronary surgery.
The department participates in several multi-disciplinary programmes.
For the ISCOMS Research Fellowships we require an open minded student, with basic statistics skills. The student must be able to speak English fluently and write correctly.
Project K: Understanding the pathophysiology of SHOCK-mediated organ failure in order to improve the clinical care of critically ill patients
Supervisor: Jill Moser PhD
Department: of Critical Care
Every day, critically ill patients in ICU’s worldwide develop failure of vital organs. This happens 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 and mortality persists long after their ICU stay. 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 supportive care 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-induced kidney failure 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. In these studies a variety of experimental techniques including immunostaining, western blotting, qRT-PCR and ELISA are used to analyse in vitro cell studies, kidney tissue from in vivo sepsis models and patient material.
Project L: Next Generation Sequencing in the Clinical Microlab.
Supervisor: John W.A. Rossen PhD
Dr. John W. A. Rossen has an almost 30-year history in molecular virology/microbiology and more than 125 peer reviewed publications (H-index 29). He is Assistant Professor at the University of Groningen, PI in the research group “Genomics for Infection Prevention” of Prof. dr. Alexander W. Friedrich and head of the molecular unit which has recently 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 characterization 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 his research is focused on implementing transcriptomics and metagenomics into clinical microbiology. Several PhD students, Post-Docs and technicians work together to investigate not only patient samples but also samples taken from animals, food and water – thereby realizing the one health principle in microbiology. Currently, Dr. Rossen is involved in the supervision of 9 PhD students. He is secretary of the ESCMID study group for genomic and molecular diagnostics (ESGMD) and treasurer of the Dutch Society of Medical Microbiology.
Project M: Regulation of hematopoietic stem cells
Supervisor: Prof. Gerald Haan PhD
Department: European Institute for the Biology of Ageing (ERIBA)
The group is interested in the unique genetic and epigenetic program that distinguishes stem cells from non-stem cells. The research group of Prof 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 exploitated 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 N: Personalized medicine in patients with diabetes and tuberculosis
Supervisors: dr. J.F.M. (Job) van Boven
Department: European Institute for the Biology of Ageing (ERIBA)
The department of Clinical Pharmacy & Pharmacology of the University Medical Center Groningen (UMCG) performs preclinical, translational, and clinical research. Research is focused on personalized 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 personalized medicine include optimization 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 drug’s 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 personalized medicine in TB and diabetes treatment? What can we do to optimize adherence to treatment? To assess these issues, you can make use of our in-house database (GIANTT, www.giantt.nl) with anonymized 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 (email@example.com)
Project O: Healthy smokers with a positive response to a provocation test.
Supervisor: M. van den Berge PhD
Department: Pulmonary diseases
In pulmonology, respiratory diseases are diagnosed based on symptoms, spirometry, and a positive response to a provocation test. Healthy controls can be defined as subjects without pulmonary complaints in the past or present, with a normal spirometry and a negative response to a provocation test.
The current cohort consists of approximately 110 healthy subjects, with a forced expiratory volume in the first second (FEV1) ≥ 90%, and a negative response to methacholine (a 20% drop in FEV1 (PC20) >9.8 mg/ml). The group can be divided in four subgroups; i. never smokers <40, ii. smokers <40, iii. never smokers >40, and iv. smokers > 40. The cohort was extensively characterized with pulmonary function tests, an alternative provocation with AMP, skin-prick tests, and inflammatory markers in respiration, blood and sputum.
Unexpectedly, eight subjects had a positive response to the alternative provocation method using AMP (PC20_AMP ≤ 160 mg/ml). For three subjects this was linked to allergies (a history of rhinitis or positive skin-prick test). All eight were smokers. Smoking is previously linked to an altered response to AMP provocation in COPD patients, but a positive response in healthy smokers is new. This indicates that smoking activated the mast cells. The response to AMP therefore might be an indication that these subjects have an increased risk to develop COPD. The current project aims to further determine the underlying mechanisms of the positive AMP response to smokers. To this end, we will link it to extensive clinical and inflammatory data available in blood, sputum, and bronchial biopsies.
Project P: Diamond magnetometry for biomedical applications
Department: biomedical engineering
Supervisor: Romana Schirhagl PhD
Magnetic resonance measurements are the gold standard for structure determination in chemistry as well as in medicine. However, as magnetic resonance signals are inherently small, the spatial resolution and sensitivity are limited to a few mm or nm at best. Diamond magnetometry is a new technique, which allows magnetic resonance measurements in the nanoscale. The technology is based on a defect in diamond, which can convert a magnetic resonance signal into an optical signal, which is much easier to detect. This is so sensitive that even the small magnetic field from single electrons can be read out. While the method has been already successful in physics, my team pioneers applications in cell biology. More specifically, we aim to measure free radicals, which are generated during stress responses. To achieve this goal we need to insert diamond nanoparticle sensors into cells. Tasks in my team include further development of diamond magnetometers, surface functionalistion of diamond, and controlling the location where diamond sensors go. The IRF student will be able to see different aspects of this project to get an overview of what we are doing.
Project Q: Cell wall bound proteins of Staphylococcus aureus, putative targets for antimicrobial therapy, and in vivo detection of S. aureus infections.
Supervisor: Dr. Girbe Buist PhD
Department: Molecular Bacteriology, Medical Microbiology
Staphylococcus aureus is an opportunistic, but dangerous, community- and hospital-acquired pathogen that employs a great variety of cell wall-associated and secreted virulence factors to subvert its human host.
In a new strategy to combat life-threatening staphylococcal infections, we aim to develop a protein based vaccine or protective human antibodies for antimicrobial therapy against multi-drug resistant and highly virulent S. aureus strains. Invariant immunogenic proteins of S. aureus have been identified by a combination of proteomics, genomics, bioinformatics, and immunological approaches.
A novel approach for the isolation of secreted His-tagged target proteins in the heterologous host Lactococcus lactis has been established. Purified fragments of proteins of S. aureus are being used for identification of the specific epitopes that are recognized by sera from human and mice infected with S. aureus.
In this project the different domains of specific immunogenic secreted virulence factors of S. aureus will be cloned in the novel expression vectors for production and isolation. Activity of the isolated protein fragments will be investigated using biochemical and enzymatic techniques. Human and mice sera will be used to investigate the specific response against the protein domains to determine if specific epitopes are bound by the antibodies.
Project R: Functional effects of microRNAs in COPD pathogenesis
Department: Pathology and Medical Biology
Supervisor: Prof. H.I. Heijink PhD
COPD is one of the top leading causes of death worldwide and its prevalence is expected to increase further with the ageing of the population, yet its pathogenesis is not well understood. COPD is characterized by chronic inflammation and tissue damage in the lungs, leading to irreversible airflow limitation. Exposure to noxious gases, such as smoke and air pollution, in combination with genetic predisposition are major risk factors for COPD development. Recent studies suggest the involvement of microRNAs in the pathophysiology of the disease. We hypothesize that dysregulated expression of specific microRNAs in COPD promotes inflammatory responses and mucus hypersecretion (chronic bronchitis), leading to airway obstruction. This hypothesis will be testedell culture models. In addition to cell culture, this project will involve various molecular and immunological techniques including cell transfection, qPCR and ELISA.
Project S: Relevant health items in the development of a HRQoL instrument for transplant patients
Supervisor: Paul F.M. Krabbe PhD & Ahmad Shahabeddin Parizi, MD MPH
During the last five decades, short-term results (survival of patients and organs) have improved, due to improved immunosuppressive regimens and surgery techniques. However, in the long-term, organ transplantation is still a model of accelerated ageing for the transplanted organ as well as for the patient. By accelerated ageing, we mean that physiological changes in the body that are associated with normal ageing occur at an earlier age in post-transplant patients than in the general population. The accelerated ageing process is characterized by the increased risk of post-transplant obesity and diabetes, hypertension, dyslipidaemia, debilitating diseases such as osteoporosis, cardiovascular diseases, malignancies (especially skin cancers), (opportunistic) infectious diseases and depression. Unfortunately, this can affect all solid-organ transplants and is associated with dramatic health-related quality of life (HRQoL) reduction.
HRQoL is a multi-dimensional construct to allocate and compare each person in the wide range of health aspects which are connected to a health condition or disease. In healthcare research, the focus is more on the physical and psychological functional status, and social relations that are known as the health domains.
HRQoL instruments are necessary tools to measure health outcomes in the patients. Available instruments in the field of transplantation are domain/organ specific, lengthy, and developed from the experts’ perspective. Yet, there is not a patient-centred instrument that evaluates the perceived health status of post-transplant patients. We aim to develop a patient-centred compact (short) and attractive instrument that can be used to evaluate the HRQoL in the solid-organ transplant patients regardless the organ type.
Research question/problem definition
In this project, students will first understand what HRQoL is and how it can be measured. Then, we will look for different health items of the health status, which are essential to choose or develop an HRQoL instrument for transplant patients. Finally, students will develop a graphical representation of the health items (HealthFan) and formulate a strategy to select the most relevant health items among a set of candidate items.
Project T: Clinical decision support in obstetrics: predicting poor maternal and neonatal outcome in women with pregnancy induced hypertension or mild pre-eclampsia at term.
Supervisor: H. Groen, MD PhD
Departments: Epidemiology and Obstetrics & Gynaecology
In a recent nationwide Randomized Controlled Trial: we found that induction of labour in women with gestational hypertension (GH) or mild preeclampsia (PE) at term prevented complications without increasing the caesarean section rate (The HYPITAT study, Koopmans et al., 2009). However, it is questionable if induction of labour is the best treatment option in all patients with GH or mild PE at term. Hence; identification of patients at increased risk of developing severe maternal or neonatal morbidity is important.
In subsequent studies based on the HYPITAT data, we have assessed the prognostic capacity of clinical characteristics and laboratory findings with respect to several outcomes, such as progression to severe disease, the risk of C-section and neonatal outcome in women with GH or mild PE at term. This was done by developing prognostic models, which may aid clinicians in the counselling and treatment of individual patients. The models predict for each patient the probability of deterioration of disease or another outcome of interest.
In the proposed project you will learn how to develop a prediction model and how to evaluate its performance. SPSS will be used for the calculations, starting with basic descriptive comparisons to identify risk factors. The next step will be to use regression analysis to build the prediction model and to obtain data to evaluate discrimination (using the area under the ROC curve) and calibration.
Project U : Repair of organs with machine perfusion before transplantation
Supervisor: Prof. Henri G.D. Leuvenink PhD, Principal Investigator dept. of Surgery
Co-supervisor: Aukje Brat, PhD student and Transplant Coordinator.
Organ transplantation is a life-saving 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 kidneys. The IRF student will work together with a PhD student and will get full insight in 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. For instance, the student will perform immunohistochemical staining on sections of kidneys.
It is highly recommended for the IRF student to follow the Summer School Transplantation, which will take place in the first few days of the IRF period. For the Summer School, you will have to register separately from the IRF. For more information see the following link:
Project V : In-vivo imaging of immune cells aiming to predict outcome
Supervisor: Prof. Geke A.P. Hospers MD PHD
Department: Medical Oncology
The immune system is a complex interaction of many different cells. In many tumor types immune checkpoint blockade has shown to improve clinical outcome. But at this moment there are no robust biomarkers to predict outcome.
Molecular imaging is defined as the visualisation, characterisation, and measurement of biological processes at this molecular and cellular levels in humans and other living systems. Agents used for molecular imaging can be antibodies or other targeted drugs, radiolabeled with a radioactive isotope that allows whole body visualization with the positron emission tomography (PET) technique. In cancer, molecular imaging can be used to detect several relevant targets in vivo, as for example in breast cancer the Estrogen Receptor (ER).
In this project we will discuss/search for relevant targets for visualized immune checkpoint blockade that can be used as biomarkers to predict outcome.
Project W: Big Data and Deep Learning in Cardiology
Supervisor: Prof. Pim van der Harst PHD, Niek Verweij
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 seeking 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.