Onderzoek

1. Cardiovascular Pathology & Atherosclerosis

Prof. dr. M.J.A.P. Daemen

In the CVON Heart-Brain Connection (HBC1) program we have established a national interdisciplinary collaborative network to study, diagnose and identify potential treatment options of cognitive impairments in cardiac patients (see for instance Ciccarelli et al Cardiovasc Res 2021). The aim or our research program in the follow up HBCx program (see hart-brein) is to identify endothelial-derived circulating biomarkers for chronic cerebral hypoperfusion and relate these to cognition. One example of that research is a study in which we successfully performed RNA sequencing on human post-mortem intra- and extracranial ECs to identify their differential molecular regulation and selected in silico 59 genes involved in HD (Hermkens et al, Acta Neuropath Communic 2019). Another part of our research focusses on the specific features atherosclerosis in intracranial arteries and relate these to MRI and clinical features (van Hespen et al, Hypertension 2021).

Head of the team Mat Daemen is Full Professor of the Pathology of Atherosclerosis at the University of Amsterdam (UvA) and clinical pathologist at the Department of Pathology of Amsterdam UMC. He is vice-dean of research of Amsterdam UMC, chair of the Amsterdam Research Board and chair of Research Support of Amsterdam UMC. His research focuses on the vascular effects of cognitive impairments with a special interest in the pathological- and molecular features of intracranial atherosclerosis. He is leading a national research program on this topic, the Heart Brain Connection. He has published more than 330 papers (h-index 84). As chair of the Research&ICT steering committee of Amsterdam UMC, leader of the Health program in the Amsterdam AI technology for people initiative and hub coordinator of the Health program in the national AI coalition he promotes and supports the local and national initiatives on data science and AI in the health domain.

Team members

• Sanny Scheffer, PhD Student
• Ingeborg Waas, Technician
• Nerissa Denswil, Guest Researcher - Focus: intracranial atherosclerosis, novel circulating biomarkers of vascular cognitive impairment

Key publications pure.amc.nl

 1.    Ritz K, Denswil NP, Stam OC, van Lieshout JJ, Daemen MJ. Cause and mechanisms of intercranial atherosclerosis. Circulation. 2014 Oct 14;130(16):1407-14.

2.    Christ A, Temmerman L, Legein B, Daemen MJ, Biessen EA. Dendritic cells in cardiovascular diseas. Circulation. 2013 Dec 17;128(24):2603-13.

3.    Huveneers S, Daemen MJ, Hordijk PL. Between Rho(k) and a hard place: the relation between vessel wall stiffness, endothelial contractility, and cardiovascular disease. Circ Res. 2015 Feb 27;116(5):895-908.

4.    Scheffer S, Hermkens DMA, van der Weerd L, de Vries HE, Daemen MJAP.Vascular Hypothesis of Alzheimer Disease: Topical Review of Mouse Models. Arterioscler Thromb Vasc Biol. 2021 Apr;41(4):1265-1283.

5.    van Hespen KM, Mackaaij C, Waas ISE, de Bree MP, Zwanenburg JJM, Kuijf HJ, Daemen MJAP, Hendrikse J, Hermkens DMA. Arterial Remodeling of the Intracranial Arteries in Patients With Hypertension and Controls: A Postmortem Study. Hypertension. 2021 Jan;77(1):135-146.

6.    Daemen MJ, Ferguson MS, Gijsen FJ, Hippe DS, Kooi ME, Demarco K, van der Wal AC, Yuan C, Hatsukami TS. Carotid plaque fissure: An underestimated source of intraplaque hemorrhage. Atherosclerosis. 2016 Nov;254:102-108.

Contact: Mat Daemen 020-566 4937 Secretariaat: Christa Neering 020-566 7519

2. Cardiovascular Inflammation

Prof. dr. J.W.M. Niessen Dr. P.A.J. Krijnen

Inflammation and immunity induce and propagate heart and vessel disease and hence are key players in cardiovascular disease, in addition to infection and tissue damage. Our research group aims to identify and unravel inflammatory processes that underlie, dysfunction of the heart in myocardial infarction and myocarditis, as well as in burned skin. We are studying the pathogenic role of these processes both in the myocardium as well as the (micro)vasculature of the heart, brain and skin. Furthermore, we try to develop biomarkers that improve the diagnosis of cardiovascular diseases. Lastly, we study the efficacy of different anti-inflammatory and immunomodulatory therapies, including mesenchymal stem cell therapy, to prevent or to improve the outcome of cardiovascular disease and burn wound trauma. We thereby hope to contribute to an improved diagnosis and treatment for people with cardiovascular disease and burn trauma and to improve their quality of life.

Heads of the team

Prof. dr. Hans W.M. Niessen

Hans Niessen is a professor in Pathology with a specialized interest in cardiovascular pathology. He studies inflammatory processes and their role in heart and vessel pathology. In addition, he is studying the intricate relationship between inflammation and the progression of tissue damage as well as tissue healing in burned skin. 

Dr. Paul A.J. Krijnen

Paul Krijnen is a biologist who performed his PhD research on the roles of acute phase reactants in the adverse remodeling of the heart after myocardial infarction. Since, his research interests include the adverse roles of cellular immunity and (micro)vascular inflammation/thrombosis in myocardial infarction and myocarditis as well as in the burned skin.  

Team members

• BSc Ingeborg Waas; Research analist
• MSc Linghe Wu; PhD student into cellular inflammation in myocarditis
• MSc Amber Korn; PhD student into atherosclerosis in diabetes
• MSc Mitchell D. Fiet; PhD student into stem cell therapy for atherosclerosis
• MSc Britt van der Leeden; PhD student into NETosis-induced coagulopathy in burn wounds
• MSc Jiang Zhu; PhD student into cardiac microvascular dysfunction after cancer therapy.
• MSc Madalena L.M.P. Gomes; PhD student into extracellular matrix formation after burn wounds.

Key publications

1)    Wu L, Woudstra L, Dam TA, Germans T, van Rossum AC, Niessen HWM, Krijnen PAJ. Electrocardiographic changes are strongly correlated with the extent of cardiac inflammation in mice with Coxsackievirus B3-induced viral myocarditis. Cardiovasc Pathol. 2021;54:107367.

 2)    Korkmaz HI, Ulrich MMW, Wieringen WNV, Doǧan H, Vlig M, Emmens RW, Meyer KW, Sinnige P, Zeerleder S, Wouters D, Ham MSV, Zuijlen PPMV, Krijnen PAJ, Niessen HWM. C1 Inhibitor Administration Reduces Local Inflammation and Capillary Leakage, Without Affecting Long-term Wound Healing Parameters, in a Pig Burn Wound Model. Antiinflamm Antiallergy Agents Med Chem. 2021;20(2):150-160.

 3)    Wu L, Emmens RW, van Wezenbeek J, Stooker W, Allaart CP, Vonk ABA, van Rossum AC, Niessen HWM, Krijnen PAJ. Atrial inflammation in different atrial fibrillation subtypes and its relation with clinical risk factors. Clin Res Cardiol. 2020 Oct;109(10):1271-1281. 1)  

4) Rieckmann M, Delgobo M, Gaal C, Büchner L, Steinau P, Reshef D, Gil-Cruz C, Horst ENT, Kircher M, Reiter T, Heinze KG, Niessen HW, Krijnen PA, van der Laan AM, Piek JJ, Koch C, Wester HJ, Lapa C, Bauer WR, Ludewig B, Friedman N, Frantz S, Hofmann U, Ramos GC. Myocardial infarction triggers cardioprotective antigen-specific T helper cell responses. J Clin Invest. 2019;129(11):4922-4936.

 5) Ter Horst EN, Krijnen PAJ, Hakimzadeh N, Robbers LFHJ, Hirsch A, Nijveldt R, Lommerse I, Fontijn RD, Meinster E, Delewi R, van Royen N, Zijlstra F, van Rossum AC, van der Schoot CE, van der Pouw Kraan TCTM, Horrevoets AJ, van der Laan AM, Niessen HWM, Piek JJ. Elevated monocyte-specific type I interferon signaling correlates positively with cardiac healing in myocardial infarct patients but interferon alpha application deteriorates myocardial healing in rats. Basic Res Cardiol. 2018;114(1):1. 

6)    Woudstra L, Meinster E, VAN Haren L, Kay AM, Koopman M, Belien JAM, Morrison MC, VAN Rossum AC, Helder MN, Juffermans LJM, Niessen HWM, Krijnen PAJ. StemBell therapy stabilizes atherosclerotic plaques after myocardial infarction. Cytotherapy. 2018;20(9):1143-1154. 

7) Korkmaz HI, Ulrich MMW, Vogels S, de Wit T, van Zuijlen PPM, Krijnen PAJ, Niessen HWM. Neutrophil extracellular traps coincide with a pro-coagulant status of microcirculatory endothelium in burn wounds. Wound Repair Regen. 2017;25(4):609-617.

Contact

Prof. dr. Hans W.M. Niessen; Email: jwm.niessen@amsterdamumc.nl

Dr. Paul A.J. Krijnen; Email: paj.krijnen@amsterdamumc.nl

Prof. dr. M.J. van de Vijver, pathologist, P.I., department of Pathology, Academic Medical Center, University of Amsterdam

The research in our group is aimed at the use of genetic techniques to refine classification of solid tumors, with an emphasis on breast cancer, ovarian cancer and pancreatic cancer.
Breast cancer is presently classified based on tumor diameter, histologic type and grade, lymph node status and estrogen receptor, progesterone receptor and HER2 status. This classification has important implications for the treatment of breast cancer patients.

A more refined classification should be possible based on genetic alterations and gene expression profiles.
The genetic alterations identified in breast cancer are amplification of between 10 and 20 oncogenes and mutations in several tumor suppressor genes.
We have previously studied the genetic alterations (with a focus on HER2 gene amplification) in breast carcinomas in relation to clinical and pathological parameters.

Gene expression profiling has led to the identification of subsets of breast cancer revealed by unsupervised and supervised classification.
We have used supervised classification to identify a 70 gene prognosis profile and clinical studies are ongoing to investigate if and how this prognosis profile can be implemented in clinical practice.

The main projects on breast cancer are the identification of genetic alterations and gene expression profiles that are associated with pattern of metastasis and response to chemotherapy in patients with metastastatic breast cancer; and through participation in the EU funded BASIS project to identify genetic alterations in breast cancer in relation to histopathological features using whole genome sequence analysis and detailed histological analysis if breast carcinomas.

In ovarian cancer and pancreatic cancer we are studying heterogeneity of genetic alterations and gene expression profiles; and association with prognosis and response to therapy.

Prof. dr. C.J.M. van Noesel, pathologist, P.I., department of Pathology, Academic Medical Center, University of Amsterdam
Prof. dr. S.T. Pals, pathologist, P.I., department of Pathology, Academic Medical Center, University of Amsterdam
Dr. M. Spaargaren, P.I., department of Pathology, Academic Medical Center, University of Amsterdam
Research program dr. M. Spaargaren

Dr. Marcel Spaargaren is a medical molecular biologist at the Dept. Of Pathology, with a special interest in the molecular and cell biological aspects of the pathogenesis of B-cell malignancies, in particular multiple myeloma (MM), chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL), and the exploitation of this knowledge for clinical applications.
As a PI in the AMC, he participates in the major research themes “Oncology” and “Immunity and Infection” and as such in the Oncologic Research Center AMC (ORCA) and the Center for Immunology Amsterdam (CIA). He is dean of the Oncology Graduate School Amsterdam (OOA: Onderzoekschool Oncologie Amsterdam) for PhD students of the Netherlands Cancer Institute (NKI), Free University Medical Center (VUMC), and AMC. He is secretary of the society on Tumor Cell Biology of the Dutch Cancer Society (KWF-werkgemeenschap Tumorcel biologie), and co-founder and board-member of the Lymphoma and Myeloma Center Amsterdam (LYMMCARE).The research group of Marcel Spaargaren (Dept. of Pathology, section Immuno- and Hematopathology) has a long-standing interest in the molecular and cellular biology of B-cell differentiation and function, and in the pathogenesis of B-cell malignancies, in particular multiple myeloma (MM), non-Hodgkin lymphoma (NHL), and chronic lymphocytic leukemia (CLL).
The major themes of the current research are "Growth and differentiation of normal and malignant B cells" and "Cell adhesion and migration in immunity and cancer". In this context, the aims are: 
1) identify and molecularly dissect the signaling pathways involved in differentiation and function of B-cells and in the pathogenesis of B-cell malignancies; 
2) explore and exploit the microenvironment-dependence as the Achilles’ heel of B-cell malignancies, focussing on multiple myeloma and chronic lymphocytic leukemia.General interests include signal transduction, cell proliferation and survival, cell adhesion and migration, and tumor-microenvironment-dependence. More specifically, related to the differentiation and function of B cells and the pathogenesis of B-cell malignancies, they explore(d) the molecular and functional aspects of signalling by the B-cell antigen receptor, chemokines (e.g., CXCL12), HGF/MET, and WNTs, and the role of heparan sulfate proteoglycans (e.g., CD44 and Syndecan-1), adhesion molecules (integrins and cadherins), GTPases (e.g., Ras and Ral), kinases (e.g., Bruton’s tyrosine kinase), and transcription factors (e.g., FOXP1).

Prof. dr. E.M.A. Aronica, neuropathologist, PI, Department of Pathology, Academic Medical Center, University of Amsterdam

Research program Prof. dr. E.M.A. Aronica:

• Epilepsy
• Inflammation
• Neurodevelopmental disorders
• Brain development and ageing
• Neuroncology

Neuron-glia interactions in health and disease
Recent work on neuro-glial cell physiology has revealed that glial cells are much more actively involved in brain information processing than previously anticipated. This finding has stimulated the novel view that the brain should be viewed as a circuit of interactive neuron and glial cell networks. Despite the solidity of the evidence for glia-neuron signalling many fundamental questions on the basic cellular and molecular aspects of this intriguing partnership still remain unanswered or have not been addressed in the functional in vivo context. The major aim of our research efforts is to investigate the role of glial cells as potential cellular targets for developing novel therapies in human neurological disorders. To achieve this aim we use a multidisciplinary approach, creating a collaborative team of specialisms including neurology, neuropathology and neurobiology. In 2006 we performed large-scale studies of gene expression using experimental models and human material from patients with acute and chronic CNS injury. We provided evidence of a prominent and persistent activation of the innate immune response in various neurological disorders with different etiologies, but without a primary inflammatory pathogenesis. This response involves both astrocytes and microglial cells and is associated with the activation of several pathways which influence hyperexcitability, degeneration and regeneration.

In 2007, international collaborations have been established to further investigate the role of astroglial and microglial cells in the initiation and persistence of the inflammatory response associated with neuronal degeneration and hyperexcitability (Grant of the European Union: HEALTH-2007-2.2.1-6:“ Neuron-glia interactions in health and disease”; www.neuroglia.eu ). This has been investigated in human brain and in well established animal models of epilepsy. 

In collaboration with the group of Dr. Vezzani (Mario Negri Institute, Italy) we recently reported a proconvulsant pathway involving high-mobility group box-1 (HMGB1) release from neurons and glia and its interaction with Toll-like receptor 4 (TLR4), a key receptor of innate immunity. HMGB1-TLR4 signaling may contribute to generating and perpetuating seizures in humans and might be targeted to attain anticonvulsant effects in epilepsies that are currently resistant to drugs (Nature Medicine, 16: 413–419, 2010).

We are presently studying the role of proinflammatory signaling-associated microRNAs (miRNA). As described in the recently article published in EJN (Eur J Neurosci.; 31(6):1100-7. 9) we demonstrated in both experimental and human temporal lobe epilepsy the selective up-regulation of the on miR-146a, a microRNA that is induced by pro-inflammatory stimuli, modulating innate immunity through regulation of Toll-like receptor signaling. 

New projects starting in 2012:

1. 2012-2015: Grant of the European Union: HEALTH.2011.2.2.2-2 " Pathways common to brain development and ageing: defining strategies for preventive therapy and diagnostics “

Objectives

a. To examine neurodegeneration-related proteins during development: comparing early and postnatal developmental stages in developmental disorders

b. To examine the relationship between neurodegeneration-related proteins and specific developmental pathway. 

c. To study selected altered mRNAs, microRNAs and proteins in focal cortical malformations

2. 2012-2016: Characterization of genetic aberrations in pediatric low-grade glioneuronal tumors Stichting Kinderen Kankervrij (KiKa).

The aim of the study is to identify chromosomal changes in an international large series of GNT’s by genomic wide microarray based comparative genomic hybridization (aCGH), PCR and genomic sequencing. During the project these chromosomal changes will be investigated for their potential clinical relevance as related to prognosis, pathogenesis en epileptogenesis. The miRNA profile of GNT’s will be also evaluated. By investigating these biologic characteristics in relation to the clinical data, we can improve the diagnostics and therapy for GNT’s in children, as guided by the clinical biological risk profile of the tumor.

Prof. dr S. Florquin, Renal Pathologist, P.I., Department of Pathology, Academic Medical Center, University ofAmsterdam 

Sandrine Florquin (1965) received her MD degree from the Faculty of Medicine of the Universite Libre de Bruxelles (Belgium) in 1990, her “Thèse d’Agrégation de l’Enseignement Supérieur”from the same University in 1995, and her PhD degree (cum laude) from the University of Leiden (The Netherlands) in 1997. In 1998 she was board certified in the Netherlands in Pathology, and in 2001 in Immunology. From 1991 to 1994, she was Research Fellow of Fonds National de la Recherche Scientifique(Belgium) in the department of Immunology of Prof. M. Goldman, Université Libre de Bruxelles and in the departments Prof. B. Brenner and R. Cotran (Brigham and Women’s Hospital, Harvard University). Since 1998 Florquin is staff member of the Department of Pathology in het AMC. Her research is embedded in the Center for Immunology Amsterdam (CIA). She received several NWO-grants (Clinical Fellowship, ASPASIA and VIDI). In 2007 she was appointed Professor of Pathology in theUniversity of Amsterdam. She is a member of the Scientific Board of the Dutch Kidney Foundation and of the ERA-EDTA.

Research Programs: Renal Inflammation and REpair (RIRE)

Thanks to the financial support of NWO and Dutch Kidney Foundation, we set up a research group dedicated to unravel the immunological mechanisms involved in renal injury and repair and to design new therapeutic tools for renal diseases.

To unravel the involvement of innate immunity in the renal diseases, we used relevant rodent models for acute and chronic renal injury (ischemia-reperfusion, obstructive nephropathy, renal transplantation and pyelonephritis using knock-out mice, transgenic mice, anti-sense oligonucleotide and blocking antibodies), renal biopsies, urine and plasma of renal patients, and in vitro models (tubular epithelial cell and endothelial cell cultures).

Our research line can be divided in 4 sub-themes:

a) The role of CD44 in Renal Injury and Repair
b) The role of Pattern-Recognition Receptors (PRRs) in Renal Injury and Repair
c) The fibrinolytic and clotting systems in Renal Injury and Repair
d) Development of validated analyses of renal transplant biopsies to identify local markers
of tolerance and to predict the development of fibrosis