Research Groups

Medical Physiology

Research in the Section of Medical Physiology focuses on 1) the neuron–glia signalling in the healthy central nervous system and disturbances during healthy ageing or neurodegenerative conditions, like multiple sclerosis and Alzheimer's disease; 2) the function of ion channels and their role in neurodegenerative diseases such as spinocerebellar ataxia; and 3) the human motor neuron physiology with an emphasis on fatigue and susceptibility to fatigue in chronic diseases such as multiple sclerosis.

These research programmes contribute to and are a part of the University Medical Centre Groningen research consortium Ageing Brain and the Multiple Sclerosis Centre North Netherlands. This section contributes to the education programmes of the medical curriculum, kinesiology, dentistry and life sciences, with a focus on human physiology, neurophysiology and neuroscience.

The Section of Medical Physiology contributes to the Behavioural and Cognitive Neurosciences/Graduate School of Medical Sciences (BCN/GSMS) PhD programme and to three master programmes: BCN, Biomedical Sciences (BMS) and Medical Pharmaceutical Drug Innovation (MPDI).

  • People
  • Publications
  • Alumni
  • Microglia
  • Ion Channels
  • Motor neurons
  • Bart Eggen PhD Section Head Medical Physiology Visit
    Position

    Head of the Section Medical Physiology Professor of Molecular Neuroimmunology

    Research fields

    Neuroscience, epigenetics, innate immunity

    Head of Department
    Lecturer
    Knut Biber PhD
    Management
    PhD student
    Malte Borggrewe Msc.
    Marissa Dubbelaar B.A.Sc.
    Yang Heng Msc.
    Qiong Jiang Msc.
    Laura Kracht Msc.
    Chairi Misrielal Msc.
    Javier Gustavo Villamil Ortiz Msc.
    Roeland Prak B.Sc
    Nynke Talma Msc.
    XiaoMing Zhang MSc.
    Postdoctoral Fellow
    Practicum Coordinator
    Annelies van der Molen B.A.Sc.
    Principal Educator
    Principal Investigator
    Senior Postdoc
    Technical Support
    Tjalling Nijboer B.A.Sc.
    Technician
    • Ang CW, Jacobs BC, Laman JD. (2004) The Guillain-Barré syndrome: a true case of molecular mimicry. Trends Immunol.
    • Halzǎ,T. Hedegaard Bro, B. Bilenberg,and A. Koçer * (2013) Well-Defined Microapertures for Ion Channel Biosensors. Anal. Chem.
    • Urban, Al. Kleefen, N. Mukherjee, B. Windschiegl, P. Seelheim, M. vor der Brüggen, A. Koçer, and R. Tampé (2014) Highly parallel transport recordings on a membrane-on-nanopore chip at single molecule resolution. Nano Letters
    • Mukherjee, M. D. Jose, J. P.Birkner, M. Walko, H. I. Ingólfsson, A. Dimitrova, C. Arnarez, S. J. Marrink, A. Koçer* (2014) The activation mode of the mechanosensitive ion channel, MscL, by lysophosphatidylcholine differs from tension-induced gating. FASEB J
    • Wes PD, Holtman IR, Boddeke HWGM, Möller T, Eggen BJ (2016)Next generation transcriptomics and genomics elucidate biological complexity of microglia in health and disease. Glia
    • Biber K, Möller T, Boddeke E, Prinz M. (2016)Central nervous system myeloid cells as drug targets: current status and translational challenges. Nat Rev Drug Discov.
    • Holtman IR, Noback M, Bijlsma M, Duong KN, van der Geest MA, Ketelaars PT, Vainchtein ID, Eggen BJ*, Boddeke HWGM* (2015) Glia Open Access Database (GOAD): A Comprehensive Gene Expression Encyclopedia of Glia cells in Health and Disease. Glia
    • Schaafsma W, Zhang X, van Zomeren KC, Jacobs S, Georgieva PB, Wolf SA, Kettenmann H, Janova H, Saiepour N, Hanisch U-K, Meerlo P, van den Elsen PJ, Brouwer N, Boddeke HWGM, Eggen BJ (2015) Long-lasting pro-inflammatory suppression of microglia by LPS-preconditioning is mediated by RelB-dependent epigenetic silencing. Brain Behavior and Immunity
    • Raj DD, Moser J, van der Pol SM, van Os RP, Holtman IR, Brouwer N, Oeseburg H, Schaafsma W, Wesseling EM, den Dunnen W, Biber KP, de Vries HE, Eggen BJ, Boddeke HW (2015) Enhanced microglial pro-inflammatory response to lipopolysaccharide correlates with brain infiltration and blood-brain barrier dysregulation in a mouse model of telomere shortening. Aging Cell.
    • Muñoz-Llancao P, Henríquez DR, Wilson C, Bodaleo F, Boddeke EW, Lezoualc'h F, Schmidt M, González-Billault C.(2015) Exchange Protein Directly Activated by cAMP (EPAC) Regulates Neuronal Polarization through Rap1B. J Neurosci
    • Holtman IR, Raj DD, Miller JA, Schaafsma W, Yin Z, Brouwer N, Wes, PD, Möller T, Orre M, Kamphuis W, Hol EM, Boddeke HWGM, Eggen BJ(2015)Induction of a common microglia gene expression signature by aging and neurodegenerative conditions: a co-expression meta-analysis. Acta Neuropath Comm
    • Holtman IR, Raj DD, Miller JA, Schaafsma W, Yin Z, Brouwer N, Wes PD, Möller T, Orre M, Kamphuis W, Hol EM, Boddeke EW, Eggen BJ. (2015) Induction of a common microglia gene expression signature by aging and neurodegenerative conditions: a co-expression meta-analysis. Acta Neuropathol Commun.
    • Heneka MT, Carson MJ, El Khoury J, Landreth GE, Brosseron F, Feinstein DL, Jacobs AH, Wyss-Coray T, Vitorica J, Ransohoff RM, Herrup K, Frautschy SA, Finsen B, Brown GC, Verkhratsky A, Yamanaka K, Koistinaho J, Latz E, Halle A, Petzold GC, Town T, Morgan D, Shinohara ML, Perry VH, Holmes C, Bazan NG, Brooks DJ, Hunot S, Joseph B, Deigendesch N, Garaschuk O, Boddeke E, Dinarello CA, Breitner JC, Cole GM, Golenbock DT, Kummer MP. (2015) Neuroinflammation in Alzheimer's disease. Lancet Neurol.
    • Powell JJ, Thomas-McKay E, Thoree V, Robertson J, Hewitt RE, Skepper JN, Brown A, Hernandez-Garrido JC, Midgley PA, Gomez-Morilla I, Grime GW, Kirkby KJ, Mabbott NA, Donaldson DS, Williams IR, Rios D, Girardin SE, Haas CT, Bruggraber SF, Laman JD, Tanriver Y, Lombardi G, Lechler R, Thompson RP, Pele LC. (2015) An endogenous nanomineral chaperones luminal antigen and peptidoglycan to intestinal immune cells. Nat Nanotechnol.
    • van Luijn MM, Kreft KL, Jongsma ML, Mes SW, Wierenga-Wolf AF, van Meurs M, Melief MJ, der Kant RV, Janssen L, Janssen H, Tan R, Priatel JJ, Neefjes J, Laman JD, Hintzen RQ. (2015) Multiple sclerosis-associated CLEC16A controls HLA class II expression via late endosome biogenesis. Brain.
    • Pacheco-Torres, N. Mukherjee, M. Walko, P.López-Larrubia, P. Ballesteros, S. Cerdan and A. Koçer* (2015) Image Guided Drug Release From pH-sensitive Ion Channel-functionalized Stealth Liposomes into an in vivo Glioblastoma Model. Nanomedicine:nanotechnology, biology, and medicine
    • Wolkorte R, Heersema DJ, Zijdewind I. (2015) Muscle Fatigability During a Sustained Index Finger Abduction and Depression Scores Are Associated With Perceived Fatigue in Patients With Relapsing-Remitting Multiple Sclerosis. Neurorehabilitation Neural Repair.
    • Prak RF, Doestzada M, Thomas CK, Tepper M, Zijdewind I (2015). Reduced voluntary drive during sustained but not during brief maximal voluntary contractions in the first dorsal interosseous weakened by spinal cord injury. J Appl Physiol
    • Holtman IR, Noback M, Bijlsma M, Duong KN, van der Geest MA, Ketelaars PT, Brouwer N, Vainchtein ID, Eggen BJ, Boddeke HW. (2015) Glia Open Access Database (GOAD): A comprehensive gene expression encyclopedia of glia cells in health and disease. Glia
    • Wolkorte R, Heersema DJ, Zijdewind I (2015) Reduced Dual-Task Performance in MS Patients Is Further Decreased by Muscle Fatigue. Neurorehabil Neural Repair.
    • Stern JN, Yaari G, Vander Heiden JA, Church G, Donahue WF, Hintzen RQ, Huttner AJ, Laman JD, Nagra RM, Nylander A, Pitt D, Ramanan S, Siddiqui BA, Vigneault F, Kleinstein SH, Hafler DA, O'Connor KC. (2014) B cells populating the multiple sclerosis brain mature in the draining cervical lymph nodes. Sci Transl Med.
    • Thomas CK, Bakels R, Klein CS, Zijdewind I (2014). Human spinal cord injury: motor unit properties and behavior. Acta Physiol.
    • Konijnenberg, D. Yilmaz, H. I. Ingólfsson, Anna Dimitrova, Siewert J. Marrink, Z. Lid, C. Vénien-Bryand, F. Sobott and Koçer*(2014) Global structural changes of an ion channel during its gating are followed by ion mobility mass spectrometry. Proc Natl Acad Sci USA
    • Wolkorte R, Kamphuis J, Zijdewind I. (2014). Increased reaction times and reduced response preparation already starts at middle age. Front Aging Neurosci.
    • Raj D, Jaarsma D, Holtman IR, Olah M, Ferreira FM, Schaafsma W, Brouwer N, Meijer M, de Waard MC, van der Pluijm I, Brandt R, Kreft KL, Laman JD, de Haan G, Biber KP, Hoeijmakers JHJ, Eggen BJ, Boddeke HWGM (2014) Priming of Microglia in a DNA Repair Deficient Model of Accelerated Aging. Neurobiol of Aging
    • Vainchtein ID, Vinet J, Brouwer N, Brendecke S, Biagini G, Biber KP, Boddeke HWGM, Eggen BJ (2014) In acute experimental autoimmune encephalomyelitis, infiltrating macrophages are immune activated, whereas microglia remain immune suppressed. Glia
    • Raj DD, Jaarsma D, Holtman IR, Olah M, Ferreira FM, Schaafsma W, Brouwer N, Meijer MM, de Waard MC, van der Pluijm I, Brandt R, Kreft KL, Laman JD, de Haan G, Biber KP, Hoeijmakers JH, Eggen BJ, Boddeke HW. (2014) Priming of microglia in a DNA-repair deficient model of accelerated aging. Neurobiol Aging
    • Heetkamp J, Hortobágyi T, Zijdewind I. (2014). Increased bilateral interactions in middle-aged subjects. Front Aging Neurosci.
    • Bhat KP, Balasubramaniyan V, Vaillant B, Ezhilarasan R, Hummelink K, Hollingsworth F, Wani K, Heathcock L, James JD, Goodman LD, Conroy S, Long L, Lelic N, Wang S, Gumin J, Raj D, Kodama Y, Raghunathan A, Olar A, Joshi K, Pelloski CE, Heimberger A, Kim SH, Cahill DP, Rao G, Den Dunnen WF, Boddeke HW, Phillips HS, Nakano I, Lang FF, Colman H, Sulman EP, Aldape K. (2013) Mesenchymal differentiation mediated by NF-κB promotes radiation resistance in glioblastoma. Cancer Cell
    • Szymanski, D. Yilmaz, A. Koçer*, B.L. Feringa* (2013) Bright ion channels and lipid bilayers. Accounts of Chemical Research
    • Duarri A, Jezierska J, Fokkens M, Meijer M, Schelhaas HJ, den Dunnen WF, van Dijk F, Verschuuren-Bemelmans C, Hageman G, van de Vlies P, Küsters B, van de Warrenburg BP, Kremer B, Wijmenga C, Sinke RJ, Swertz MA, Kampinga HH, Boddeke E, Verbeek DS. (2012) Mutations in potassium channel kcnd3 cause spinocerebellar ataxia type 19. Ann Neurol
    • Steens A, de Vries A, Hemmen J, Heersema T, Heerings M, Maurits N, Zijdewind I (2012). Fatigue perceived by Multiple Sclerosis patients is associated with muscle fatigue. Neurorehab Neural Repair
    • Zijdewind I, Thomas CK (2012). Firing patterns of spontaneously active motor units in spinal cord-injured subjects. J Physiol
    • P. Birkner, B. Poolman, A. Koçer* (2012) Hydrophobic gating of Mechanosensitive channel of large conductance evidenced by single-subunit resolution.  Proc Natl Acad Sci USA
    • Biber K, Tsuda M, Tozaki-Saitoh H, Tsukamoto K, Toyomitsu E, Masuda T, Boddeke H, Inoue K. (2011) Neuronal CCL21 up-regulates microglia P2X4 expression and initiates neuropathic pain development Embo J.
    • Jagessar SA, Kap YS, Heijmans N, van Driel N, van Straalen L, Bajramovic JJ, Brok HP, Blezer EL, Bauer J, Laman JD, 't Hart BA. (2010) Induction of progressive demyelinating autoimmune encephalomyelitis in common marmoset monkeys using MOG34-56 peptide in incomplete freund adjuvant. J Neuropathol Exp Neurol.
    • Roosink M, Zijdewind I (2010). Corticospinal excitability during observation and imagery of simple and complex hand tasks: implications for motor rehabilitation. PLOS One
    • Kooistra SM, van den Boom V, Thummer RP, Johannes F, Wardenaar R, Tesson BM, Veenhoff LM, Fusetti F, O’Neill LP, Turner BM, de Haan G, Eggen BJ (2010) UTF1 regulates ES cell chromatin organization and gene expression. Stem Cells
    • van der Fits L, Mourits S, Voerman JS, Kant M, Boon L, Laman JD, Cornelissen F, Mus AM, Florencia E, Prens EP, Lubberts E. (2009) Imiquimod-induced psoriasis-like skin inflammation in mice is mediated via the IL-23/IL-17 axis. J Immunol.
    • 't Hart BA, Hintzen RQ, Laman JD. (2009) Multiple sclerosis - a response-to-damage model. Trends Mol Med.
    • van Zwam M, Huizinga R, Heijmans N, van Meurs M, Wierenga-Wolf AF, Melief MJ, Hintzen RQ, 't Hart BA, Amor S, Boven LA, Laman JD. (2009) Surgical excision of CNS-draining lymph nodes reduces relapse severity in chronic-relapsing experimental autoimmune encephalomyelitis. J Pathol.
    • Post M, Bakels, R, Zijdewind I (2009). Inadvertent contralateral activity during a sustained unilateral contraction reflects the direction of target movement. J Neuroscience
    • Koçer*, M. Walko, B. L. Feringa*. (2007) Synthesis and Utilization of reversible and irreversible light-activated nanovalves derived from the channel protein MscL. Nature Protocols
    • Plaza-Menacho I, van der Sluis T, Hollema H, Gimm O, Buys CH, Magee AI, Isacke CM, Hofstra RM, Eggen BJ (2007) Ras/ERK1/2-mediated STAT3 Ser727 phosphorylation by familial medullary thyroid carcinoma-associated RET mutants induces full activation of STAT3 and is required for c-fos promoter activation, cell mitogenicity, and transformation. J Biol Chem
    • van den Boom V, Kooistra SM, Boesjes M, Geverts B, Houtsmuller AB, Monzen K, Komuro I, Essers J, Drenth-Diephuis LJ, Eggen BJ (2007) UTF1 is a chromatin-associated protein involved in ES cell differentiation. J Cell Biol
    • Visser L, Melief MJ, van Riel D, van Meurs M, Sick EA, Inamura S, Bajramovic JJ, Amor S, Hintzen RQ, Boven LA, 't Hart BA, Laman JD. (2006) Phagocytes containing a disease-promoting Toll-like receptor/Nod ligand are present in the brain during demyelinating disease in primates. Am J Pathol.
    • A. Koçer, M. Walko, E. Bulten, E. Halza, B. L. Feringa, W. Meijberg. (2006) Rationally Designed Chemical Modulators Convert a Bacterial Channel Protein into a pH-Sensory Valve. Angew. Chem. Int. Ed.
    • Koçer, M. Walko, W. Meijberg, B. L. Feringa. (2005) A Light-Actuated Nanovalve Derived from a Channel Protein. Science 
    • Benus GF, Wierenga AT, de Gorter DJ, Schuringa JJ, van Bennekum AM, Drenth-Diephuis LJ, Vellenga E, Eggen BJ (2005)Inhibition of the Transforming Growth Factor β (TGFβ) Pathway by Interleukin-1β Is Mediated through TGFβ-activated Kinase 1 Phosphorylation of SMAD3. Mol Biol Cell
    • 't Hart BA, Laman JD, Bauer J, Blezer E, van Kooyk Y, Hintzen RQ. (2004) Modelling of multiple sclerosis: lessons learned in a non-human primate. Lancet Neurol.
    • de Vos AF, van Meurs M, Brok HP, Boven LA, Hintzen RQ, van der Valk P, Ravid R, Rensing S, Boon L, 't Hart BA, Laman JD. (2002) Transfer of central nervous system autoantigens and presentation in secondary lymphoid organs. J Immunol.
    • Schrijver IA, van Meurs M, Melief MJ, Wim Ang C, Buljevac D, Ravid R, Hazenberg MP, Laman JD. (2001) Bacterial peptidoglycan and immune reactivity in the central nervous system in multiple sclerosis. Brain
  • Armagan Kocer laboratory

    • Dr Martin Walko (2009), Institute of Chemistry, Faculty of Science, P.J. Safarik University, Slovakia (Assistant Professor)
    • Dr Erik Halza (2011), Syncom BV (Research Scientist)
    • Dr Jan Peter Birkner (2012), University of Groningen (Zernike Institute, Research Manager)
    • Dr Nobina Mukherjee (2014), Oxford University, Department of Chemistry (Postdoctoral Fellow)
    • Dr Duygu Yilmaz (2014), ProQR, Leiden (Research Scientist)
    • Dr Mac Donald Jose (expected graduation 2015), University of Malawi, Zomba, Malawi (Researcher)

    Bart Eggen laboratory

    • Drs. W. Schaafsma (2014), Histocell Tissue Engineering, Bilbao, Spain (Project Leader)
    • Dr V. Kannan (2014)
    • Dr R.P. Thummer (2010), Department of Biosciences and Bioengineering, Indian Institute of Technology, Guwahati, India (Assistant Professor)
    • Dr. Duco Schriemer (2016)
    • Dr I.R Holtman (2016), Glass Laboratory, School of Medicine, University of California, San Diego
    • Dr. I. D. Vainchtein (2016), Molofsky Laboratory, School of Medicine, University of California, San Fransisco
    • Dr D.D.A. Raj (2016) Department of Translational Neuroscience, UMC Utrecht

    Inge Zijdewind laboratory

    • Dr Ria Wolkorte (2015) Erasmus MC
    • Dr Marijn Post (2008), Wageningen UR Library, Wageningen University
    • Dr Hiske van Duinen (2006), Department of Neuroscience, UMCG (Lecturer)

    Jon Laman laboratory

    • Former laboratory members who have established independent groups and obtained associate or full professorships: Björn E. Clausen (Mainz), Rudi W. Hendriks, Bart C. Jacobs and Erik Lubberts (Rotterdam)
    • Former postdoctoral investigators (in reverse chronological order): Marvin van Luijn, Evert Verbraak and Leonie A. Boven
    • Former PhD students (in reverse chronological order): Mathilde Girard-Madoux, Karim K. Kreft, S. Anwar Jagessar, Rinze Neuteboom, Hessel van der Zee, Yolanda S. Kap, Fleur E. van der Geijn, Emöke Ràcz, Maarten G. Wolf, Marloes van Zwam, Ruth G. Huizinga, Marieke Emonts, Manon Oude Nijhuis, Carin P.W. Geleijns, Lizette Visser, Arjen R. Companjen, C. Wim Ang, Ingrid A. Schrijver and Catharina B.M. Maasssen

    Current career tracks of alumni: medical specialization (rheumatology, dermatology, medical microbiology, neurology, paediatric infectiology), laboratory specialization (clinical chemistry), pharmaceutical and biotech industry (research or management, Crucell, Merck Serono) and national (postdoc positions, associate and full professorships) and international academic research positions (full professorship, postdoc positions)

  • Microglia (brain macrophages) are the primary immune cells of the central nervous system and perform continuous surveillance to maintain brain tissue homeostasis. The microglia respond to neuronal stress and damage. Sustained activation of the microglia results in exaggerated inflammatory activation and subsequent tissue damage, which is observed in neurodegenerative diseases.

    Alternatively, inflammation and neuroinflammation can induce a state of suppressed immune activity in the microglia, called endotoxin tolerance. This condition is associated with reduced neuronal support by the microglia and a decreased capacity to respond to inflammatory stimuli. The research is focused on neuron–glia signalling and on the epigenetic regulation of different microglia phenotypes and associated functionalities with an emphasis on brain ageing and neurodegenerative conditions.

     

    Imaris Snapshot

    The investigators combine cell and organotypical slice cultures, mouse genetics, state-of-the-art cell isolation procedures in combination with genetic and epigenetic tools to delineate the molecular and epigenetic pathways that determine microglia function. Our studies provide a genome-wide insight in the genetic and epigenetic regulation of microglia function in the normal and diseased brain and could lead to the identification of novel therapeutic targets.

    The Section of Medical Physiology is creator of the Glia Open Access Database (GOAD) which is a comprehensive web-based tool to access and analyse glia transcriptome data without having to perform all the involved bioinformatics. The tool has several features to compare and quantify gene expression and differences between samples of interest.

     

  • Ion channels are proteins present in the cell membrane of both animal and plant tissues but are particularly present in the nervous system and heart where they transmit electrical signals. Their main function is to identify, select and guide specific ions and to respond to electrical, chemical and mechanical signals to regulate a variety of processes in a cell.

     

    try05b-edit

    Our scientists are interested in exploring the mechanism of these membrane proteins and their potential applications to solve societal problems. The majority of the work has been performed on mechanosensitive ion channels and on their applications in drug delivery systems and biosensors.

    Recently, our researchers have expanded their interest to ion channels involved in neurodegenerative diseases. We study the voltage-gated potassium channel Kv4.3 at the single-molecule level, to understand how it works, how its function is modulated by accessory proteins and how its mutants cause neuronal death.

    Our scientists have core competencies in the areas of synthetic biology, biochemistry, biophysics, and electrophysiology.

     

  • Fatigue (both the perception of fatigue and fatigability) is an important debilitating and frequently occurring symptom in several patients, but also in the elderly population. Despite the high incidence, underlying mechanisms are still unknown. Our investigators use force measurements, electromyography, and functional magnetic brain resonance to investigate fatigue-related changes at the level of muscles, spine, and cortex. These neurophysiological measures are associated with measures of fatigue perception.

    EMG-Amplifier

    Fatigue is also used to stress the motor system to reveal basic principles of neuronal control of movement. During fatiguing contractions, cortical (motor-) areas increase their activity, and non-motor areas become active. This secondary effect of fatigue can result in a deterioration of cognitive task performance in both control and patient populations.

    Our investigators study motor control across the age span in healthy volunteers and in people with multiple sclerosis, minimal traumatic brain injury or spinal cord injury.

     

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