Group name: Metabolic Pathway
Engineering & Screening
Location: DSM Life Science Products, Delft
Web page:
E-Mail: Roel.Bovenberg@dsm.com
Phone:
Relevant research
interests:
-
bij DSM is de belangstelling
voor "Systems Biology" sterk groeiende
-
gebaseerd op onze jarenlange
ervaring met Metabole Engineering van
-
microbiele produktie systemen
enerzijds
en snelle ontwikkelingen op het
gebied van Genoomanalyse en BioIT
-
anderzijds
-
beide activiteiten zijn
speerpunten in ons lange termijn onderzoek
-
en worden intensief met externe
partners ontwikkeld en beoefend
Current system biology
activities:
-Intern zijn wij bezig een DSM platform voor
Systems Biology te formeren, waarin integratie van kennis en vaardigheden uit
verschillende projecten en systemen
gecoordineerd wordt
- Voorbeelden van door ons gebruikte
systemensystemen: S. cerevisiae, E coli, Aspergillus niger,
Penicillium chrysogenum, Propionibacterium, Streptomyces clavuligerus, .... tbv productie van
eiwitten, metabolieten, biomassa,
- In alle gevallen is sprake van permanente
optimalisatie van bestaande bioprocessen en daarin gebruikte micro-organismen
- Daarnaast zien we stijgende aantal compleet
nieuwe biosynthese processen door toepassing van Metabole Pathway Engineering
technieken
- Alles bij elkaar opgeteld beschikken we intern
inmiddels over een behoorlijke groep ervaren onderzoekers met elkaar
overlappende expertisegebieden (van
basale genetica t/m proces
technologen en modeleurs) + benodigde equipment om tot relevant en kwalitatief
goed onderzoek op dit gebied te komen.
Relevant collaborations (e.g.):
Internationaal hebben we goede
contacten op dit gebied in Duitsland, Denemarken en de USA en oa met de
voormalige UEF (ME conferences)
-----------------------------------------------------------------------------------------------------------
Group name: Molecular Biology
& Microbial Food Safety SILS (co-sponsored
University Chair 50% UvA, 50% Unilever Research & Deveelopment):
Other staff members involved: Hans van der Spek (UD), Gertien Smits (UD), Marian de Jong (technician UvA),Femke Mensonides (PhD -end 2003)/ Pepijn Boeree PhD (2007), Alex
ter Beek PhD (2006), Martha Arthal Sanz PhD (2004), Esther Willems
technician (2004), Andrea O'Brien Post-doc (STW 2006), Bart Keijser (EET
2005), Sharon Mithoe (technician EET 2005), Catarina Resende
(Marie-Curie EU 2004)
Location: Swammerdam Institute for Life Sciences, BCA,
University of Amsterdam
Web page: http://www.science.uva.nl/research/sils
E-Mail: brul@science.uva.nl
Phone: 31-20-5257079; mobile:31-0651378726; fax: 31-20-5256971
Relevant research
interests:
The interaction between microorganisms and
their environment studied at the cellular level using in particular novel
genomics tools. Together with the Microbial Physiology Chair at SILS the focus
is on studying in an integral way the transcriptome, proteome and metabolome of
microbial cells in the context of their (natural) environment. Main model
systems are bacillus subtilis and bakers'yeast Saccharomyces cerevisiae.
In the former we study the behaviour of the general and more specific stress
response systems such as the sigmaB regulated system and the sporulation
pathway respectively. In S. cerevisiae our focus is on an assessment of
the response of cells to heat stress and treatment with weak organic acid food
preservatives in articular sorbic and benzoic acid. In particular we focus our
work together with the microbiology group on the interaction between the
antimicrobial compound, its effect on cellular growth, its effect on cellular
metabolism and its effect on the signalling status of main cellular stress
response pathways. Finally we study genome-wide the events that take place
during the lag-phase of growth when microbial cells adapt to new environmental
constraints and thus the dynamics of this adaptation may be
unveiled. A prime new area is the study of host-pathogen
interaction. For the latter we are in the proces of developing Caenorhabditis
elegans as a model host in infection studies with Salmonella typhimurium
and in particular Campylobacter jejuni. Our studies focus on using both
genomics approaches towards the identification of host-factors in interacting
with the pathogens and at the level of the bacterial pathogens themselves. The
views we have on applying systems biology principles in this area are
extensively discussed in various recent reviews.
Relevant collaborations (e.g.):
Current collaborations in the Netherlands with respect to applied research focus on application of genomics tools in the understanding of stress resistance of microbial cells in food preservation together with TNO-Food Research, Wageningen University and the Wageningen Centre for Food Sciences, Unilever Research & Development. In addition there are major links with EU groups active in the field of novel preservation techniques and (food) molecular (micro)biology in University College London and Vienna. Recently a framework V project was started as a sub-contractor of Unilever Research & Development, on the mode-of-action and application at low temperatures of high pressure processing was the focal point of study.
Representative
publications (possibly links to pdf files):
Klis, FM, Mol P, Hellingwerf KJ and Brul S (2002) Dynamics in cell wall
structure in S. cerevisiae FEMS Microbiol. Rev. 738,1-18
Brul, S, Coote, P, Oomes, SJC,Mensonides FIC and Klis FM (2002)
Physiological action of preservative agent: prospective of use of modern microbiological
techniques in assessing microbial behaviour in food preservation Int. J. Food
Microbiol. 79, 55-64
Brul, S, Klis, FM, Oomes, SJCM, Montijn RC,Schuren
FHJ, Coote P, Hellingwerf (200) Detailed process design based on genomics of
survivors of food preservation processes Trends Food Sci. Technol. 13, 325-333.
-----------------------------------------------------------------------------------------------------------
Group name: Plant Cell Biology
Location: Wageningen University
Web page:
E-Mail: annemie.emons@wur.nl
Phone: +31 317 484329 (2155 secretary, 4329 fax)
Relevant research interests:
At the
system level the cell consists of networks of pathways, motifs, and modules
with dynamic relationships. One of these networks is the 'Transportome', the
infrastructure of the cell consisting of the cytoskeleton of microtubules and
actin filaments as its backbone and the cytoskeleton-binding proteins as its
regulators. The transportome organises the cell by being the transport highway
and is receiver of topological signals. The infrastructure determines when cell
processes occur where, an organisational regulation as vital for cells as for
human society. My research focuses on the role of the transportome in plant
cell division, elongation and cell wall formation. Research in my group and
collaboration with (theoretical) physicists are opening up the possibilities to
understand physical aspects of cell infrastructure and its regulation by
combining in vivo, in vitro and in silico approaches.
Current system biology activities:
In the systems biology approach all available data
about collective properties arising from the properties of the underlying
components and their interactions are quantified and used to make mathematical
models that can be solved to predict the behaviour of those molecules in
various cellular circumstances. The geometrical cell wall model that we have
made (Emons 1994, Plant Cell Environment) and worked out together with
theoretical physicist professor B.M. Mulder (Emons and Mulder 1998 PNAS, Mulder
and Emons 2001 J. Math. Biol.), and applied (Emons et al. 2002, Plant Biology),
is one of the first 'System' models in plant cell biology. It addresses the
question of cellulose organisation in the cell wall and predicts wall
architecture from the number of active cellulose synthases in the plasma
membrane.
-----------------------------------------------------------------------------------------------------------
Group name: Molecular Microbial Physiology
Other group staff members:
Crielaard, Teixeira de Mattos, Klis
Location: Swammerdam Institute for Life Sciences, BCA, University of Amsterdam
Web page: http://bioicrs6.chem.uva.nl/microbio/index.html, http://www.science.uva.nl//sils/
E-Mail: khelling@science.uva.nl
Phone: +31 20 5257055
Relevant research interests:
In the research group Molecular
Microbial Physiology (SILS, UvA; staff members: Crielaard, Teixeira de
Mattos, Klis and Hellingwerf) the central research topic is the molecular basis
of adaptation of microorganisms to (stress) signals from their environment.
These studies cover the (sub)molecular and (inter)cellular levels. As stress
signals we use e.g. (UV) light, high-temperature, weak acid
preservatives, nutrient limitation, etc. Part of this work is very chemically
(i.e. molecularly) oriented in the sense that we try to understand the
rearrangements within molecules that are required for these responses. At the
other extreme we try to understand how this responsiveness helps organisms to
increase their evolutionary competitiveness in the environment.
Current system biology activities:
At the central level in our research, therefore, we
try to generate an overview of the mechanisms and pathways that are available
for responses and adaptation, in a limited number of strategically chosen model
organisms (like Escherichia coli, Bacillus subtilis and Saccharomyces
cerevisiae). In addition to that, we want to understand how these pathways interact,
to jointly generate the phenotype of an organism, as it is observable in a
model system like the chemostat and/or in the natural environment. In other
words, in this part of our research program we try to understand the rationale
of why physiology and adaptation is organized the way it is. We consider this
the heart of ‘systems biology’.
On
basis of the info above my estimate is that more than half of our efforts are
within the area of ‘systems biology’. We tackle the challenges and problems in
this area with the tools of biochemistry, physiology, molecular genetics and
bioinformatics. I think that additional expertise at the level of mathematics
and statistical physics is required to significantly increase the quality of
future work in this field. The work of Uri Alon (Weizmann Institute) is a good
example of how and in which direction this field is, and will be further,
progressing.
-----------------------------------------------------------------------------------------------------------
Group name: Genomics Laboratory
Other staff members involved:
Location: University Medical Center Utrecht
Web page:
E-Mail: f.c.p.holstege@med.uu.nl
Phone: +31 30 2538186; fax +31 30 2539035
Relevant research interests:
De onderzoeksgroep die ik in
Utrecht aan het opzetten ben werkt aan
genoom-brede ontrafeling van
transcriptieregulatie mechanismen. We hebben
een aantal projecten (deels
voortzetting van mijn postdoc werk in VS) die
zeer goed passen binnen een systems
benadering van regulatie processen.
Current system biology
activities:
Binnen eventueel te vormen
netwerken kunnen wij in ieder geval onze
microarrays beschikbaar maken.
Ze zijn ontwikkeld om accuraat veranderingen
weer te geven (dankzij
optimalisatie van protocollen mbv externe controles)
en ze zijn in staat om grote of
ongebalanceerde mRNA populatie veranderingen
te meten. Hiernaast kunnen wij ook inbrengen onze
recente ervaringen met interactie-screening alsook ervaringen met het
combineren van verschillende soorten genoom-brede datasets.
-----------------------------------------------------------------------------------------------------------
Group name:
Department of Pathology
Other staff members: Wim Vermeulen, Jan Hoeijmakers, Roland Kanaar
Location: Josephine Nefkens
Institute, Erasmus University Rotterdam
Web page:
E-Mail: houtsmuller@path.fgg.eur.nl
Phone: +31 10 4088 456
Relevant research interests:
At present, enormous amounts of data are
being generated by several types of large-scale genomics and proteomics
research. Computer-aided analysis methodology (‘bioinformatics’) for the
interpretation of this data is currently an intensively explored area, and co-ordinated
efforts are being made in many institutes to install this methodology in
bioinformatics core facilities. However, to fully understand, predict (and
interfere with) the complexity of cellular (dys)function, further in-depth
study of the specific proteins and pathways elucidated with the above
approaches is required.
The rapid development of
green fluorescent protein (GFP) technology and continuous innovation of digital
imaging equipment and quantitative fluorescence assays have revolutionised the
study of proteins and protein-protein interactions in living cells. At present,
several research groups within the Erasmus MC (and co-operating groups in other
institutes) have embarked upon this novel, challenging area of research to
explore vital cellular processes including gene transcription regulation, DNA
repair and telomere function in the living cell. The
research aims at unravelling the reaction mechanisms of these processes and to
dissect the nature and order of consecutive reaction steps. In addition, the
developed technology offers new opportunities to study (therapeutic)
interference with protein function and interactions, opening the way to develop
and apply novel (high throughput) screening methodology to find new targets for
cancer therapy.
Briefly, in this
type of research the dynamic
properties of and interactions between fluorescently labeled proteins are
determined in vivo using time-lapse
microscopic imaging and state-of-the-art quantitative fluorescence assays. For translation of the massive amount of complex data
(obtained by these and other ‘-omics’
approaches) into physical properties of individual protein activities and, most
important, for understanding the complexity of multiple protein-protein
interactions in different cellular processes (‘molecular networks’), and
interaction between these processes, computer modelling is indispensable.
Current system biology activities:
The primary goal of our current
research in ‘systems biology’ is to create a computer modelling environment that
serves as an interface between experiment-based
computer modelling and computer-model-based experiments. This approach is expected to advance our
knowledge of 1), the in vivo
behaviour and interactions of cellular proteins in the context of the processes
they are involved in, 2) the interaction/cross-talk between these processes, 3) the molecular changes (eg. by mutations) that affect the proper regulation of these
processes, and/or the interaction between these processes, leading to malignant
growth, and 4) the action mechanisms of methods to interfere with these
(deviant) processes.
Relevant collaborations:
Representative publications (possibly links to pdf
files):
1. Houtsmuller
A.B., Rademakers S., Nigg A.L., Hoogstraten D., Hoeijmakers J.H.J. and Vermeulen
W. Action of DNA repair endonuclease ERCC1/XPF in living cells. Science 284, 958-961 (1999).
2. Essers
J., Houtsmuller A.B., van Veelen L.., Paulusma C., Nigg A.L., Pastink A.,
Vermeulen W., Hoeijmakers J.H.J. and Kanaar R. Nuclear dynamics of RAD52 group
homologous recombination proteins in response to DNA damage. EMBO J.
21, 2030-2037 (2002).
3. Hoogstraten
D., Nigg A.L., Heath H., Mullenders L.H.F., van Driel R., Hoeijmakers J.H.J.,
Vermeulen W. and Houtsmuller A.B. Rapid switching of TFIIH between RNA polymerase
I and II transcription and DNA repair in vivo. Mol Cell 10: 1163-1174 (2002).
4. Houtsmuller
A.B. and Vermeulen W. Macromolecular dynamics in living cell nuclei revealed by
fluorescence redistribution after photobleaching. Histochem Cell Biol 5, 13-21 (2001).
-----------------------------------------------------------------------------------------------------------
Group name: Section of Biomedical NMR, Department of
Biomedical Engineering
Location: Eindhoven University of Technology
Web page: <http://www.bmi2.bmt.tue.nl/nmr/>
E-Mail: <mailto:k.nicolay@tue.nl>
Phone: +31 40 247 5789 / 247 3787
Relevant research interests:
-
The regulation of the ATP synthesizing activity of
the mitochondrion in skeletal and cardiac muscle in health and disease
(diabetes, critical illness, genetic disorders);
-
The relation between muscle phenotype (fast-twitch,
slow-twitch) and mitochondrial characteristics;
-
The use of non-invasive NMR techniques to measure
bio-energetic properties, and in particular mitochondrial activity, in muscle
in animal models and man;
-
The integration of in vitro studies on
isolated mitochondria, skinned muscle fibers and excised muscles with in
vivo studies to determine mass flow and concentration control
characteristics at different levels of eukaryotic system organization. The
combination of molecular biological (transgenic mice), biophysical (NMR) and
modelling techniques to understand adaptive changes in mitochondrial control
characteristics in response to gain or loss of enzyme function.
Current system biology activities:
-
Biochemical, biophysical and physiological studies of
skeletal and cardiac muscle of mice deficient in creatine kinase iso-enzymes.
Experimentation and modelling are combined at several in vitro and in
vivo levels of biocomplexity to learn to understand alterations in
mitochondrial and muscle phenotype.
-
Combined animal model and human studies to measure,
understand and therapeutically alter mitochondrial and phenotype muscle in
control and diseased states.
Relevant collaborations:
-
National: - Jeneson (UU)
- Wagenmakers, Van der Vusse
(UM)
- International: - De Graaf,
Rothman (Yale)
-
Walliman (ETH)
- Wilson (MSU)
- Gellerich (Halle)
-----------------------------------------------------------------------------------------------------------
Group name: Neurons
and Networks
Location: Netherlands Institute for
Brain Research
Web page:
E-Mail: A.van.Ooyen@nih.knaw.nl
Phone:
Relevant research interests:
·
How molecular and cellular mechanisms involved in
neurite elongation and branching—the dynamics of the actin and microtubule
cytoskeletons and their modulators—lead to the generation of dendritic tree
morphology.
·
The role of the actin and microtubule dynamics in the
motility and shape changes (e.g. outgrowth and retraction of filopodia) of
growth cones.
Current system biology activities:
Relevant
collaborations (e.g.):
Representative publications (possibly links to pdf
files):
-----------------------------------------------------------------------------------------------------------
Group name:
Theoretical Biology
Location: Eindhoven University of
Technology
Web page:
E-Mail: A.V.Panfilov@bio.uu.nl
Phone: +31-30-2533694
Relevant research interests:
-
We are interested in developing of a 'silicon human
cardiac cell' and its incorporation to the virtual human heart in order to
understand the mechanisms of cardiac arrhythmias and develop new ways (new
drugs) for their management.
Current system biology activities:
-
Our group is working on development of human cardiac
cell models. Recently we have developed one of the first human ventricular cell
models (together with D.Noble Oxford), which describes cardiac excitation via
12 ionic gates. We plan to refine this model in near future by better
description of ionic currents and by including the description of the
metabolism. The metabolism is of great
importance for ATP-dependent currents, which play a major role during various
cardiac diseases (e.g. ischemia). Some recent experimental data also show
importance of gene expression during various cardiological diseases. Hence, we
would be interested to include gene regulation processes to our model in
future. Our main objective is to develop the best electrophysiological model of
human cardiac cell and using computer modeling extend it to the whole organ
with the aim to study mechanisms of cardiac arrhythmias in human heart. Note,
that the realistic modeling is probably the only possibility to study
arhythmogenesis in human heart, as cardiac arrhythmias involve the whole organ
and their experimental and clinical studies are very limited. Thus, we would be
also interested if the System Biology program includes not only 'cardiac
silicon cell' development but also few applications of that 'cells', which
could go beyond the cellular level.
-
.
Relevant collaborations:
Possible Dutch collaborations inside this
project. On metabolism with Hans
Westerhoff. On model development with Physiology of AMC (R. Wilders), on cell
connections and arhythmogenesis with Medical Physiology UMC (former Habo
Jongsma group).
-----------------------------------------------------------------------------------------------------------
Group name: PDEs in the Life Sciences
Other staff members
involved: R. Planque
(mathematical modelling), Joke Blom,
Jason Frank,
Johannes Krottje, Nga Pham Thi, Ben Sommeijer, Jan Verwer (all
scientific
computing)
Location: Centrum voor Wiskunde en Informatica,
Amsterdam
Web page: http://www.cwi.nl/projects/pdels
E-Mail: peletier@cwi.nl
Phone: +31 20 592 4226 (fax +31 20 592 4199)
Relevant research
interests:
Our group focuses on
numerical and theoretical analysis of partial differential equations, with an
eye on applications in the life sciences. On the numerical side we place the
emphasis on methods that are adaptive in both space and time, allowing us to
handle systems with strong spatial gradients and stiff time
discretizations. Simultaneously we use
and develop theoretical methods to gain qualitative and quantitative
understanding of the systems involved.
Current system
biology activities:
* Relation between diffusive gradients, metabolic control analysis, andsignal transport (with the Westerhoff group and Kholodenko)
* Axonal growth cones: relation between local rules and resulting axonal connections (bundling and debundling) (with Van Pelt and Van Ooijen)
* Continuum models for lipid bilayers
* Integration of modularity, adaptive simplification, and local particle descriptions into PDE-based simulations (with Kaandorp, Van Schuppen, and the Westerhoff group)
Relevant collaborations (see above):
Representative
publications (possibly links to pdf files):
B. Lastdrager, Numerical solution of mixed gradient-diffusion equations
modelling axon growth, Technical Report MAS-R0203 Centrum voor
Wiskunde en Informatica, P.O. Box 94079, 1090 GB AMsterdam, The Netherlands,
January 2002.
Christof Francke, Pieter W. Postma, Hans V. Westerhoff, Joke G. Blom,
and Mark A. Peletier, Why the Phosphotransferase System of Escherichia
coli Escapes the Diffusion Limitation of Signal Transduction, Transport and
Metabolism that Confronts Mammalian
Cells, CWI Report MAS-R0218 Accepted
for publication in Biophys. J.
M.A. Peletier, H.V. Westerhoff, and B.N. Kholodenko, Control of
Spatially Heterogeneous and Time-varying Cellular Reaction Networks: A New
Summation Law, CWI Report MAS-R0226
Submitted to Biophys. J.
J.G. Blom and M.A. Peletier, A continuum model of lipid bilayers CWI
Report MAS-R0229 Submitted to Euro. Jnl of Applied Mathematics.
-----------------------------------------------------------------------------------------------------------
Group name: Department of Biochemistry
Location: University
of Groningen
Web page: http://www.chem.rug.nl/enzymology/
E-Mail: b.poolman@chem.rug.nl
Phone: +31 50 3634190 (secr. 4209; Fax 4165)
Relevant research interests:
A large part of the activities in my
group is aimed understanding the regulation of the cell volume in prokaryotes.
We have identified the major components involved in osmoregulation in Lactococcus
lactis (genes have been cloned, relevant knockouts have been constructed,
proteins have been purified and studied in vitro, e.g., refs. 1
and 2), including transporters, mechanosensitive channel proteins and
transcription factors, and we are beginning to understand their osmoregulated
activites. The next step is to analyze their activities at the transcriptome
and proteome level but also to determine the changes in the lipid component of
the cell (‘lipidome’). When a cell is confronted with osmotic stress, the cell
volume increases (downshift) or decreases (upshift) and this results in changes
in the ionic strength and crowdedness of the cytoplasm, factors that influence
different steps in the osmoregulation of L.lactis.
The next step is to analyze the effect of cellular
ionic strength and crowding on the expression and activities of other
macromolecules in the cell. The majority of these molecules will not be
directly involved in osmoregulation but their function will be affected by the
consequences of osmotic stress. There are many indications that under
physiologically realistic ‘crowded’ conditions several cellular components
function differently than in diluted aqueous media. Even more dramatic, certain
intrinsically disordered proteins gain structure (and activity) under crowded
conditions. These systems will be sensitive to osmotic stress and a systematic
genome/proteome-wide and numerical approach is needed to ultimately understand
the responses of the cell.
Current system biology activities:
Initial experiments to determine the
consequences of osmotic stress at the transcriptome level are underway
(together with Oscar Kuipers). Ultrastructural and biochemical analyses of the
cell envelope are carried out in parallel; (membrane) proteome studies will
follow later.
Why L. lactis? Relatively simple organism with little redundancy at the genome level;
well-established genetics and biochemistry. Realistic possibilities in terms of
Systems Biology.
Why cell volume regulation? Important, generic and well-defined “SubSystems Biology” problem that
lends itself to an elucidation of the systems properties.
Relevant
collaborations (e.g.):
Representative publications
(possibly links to pdf files):
Heide,
T. van der, Stuart, M.C.A., and Poolman, B. (2001) On the osmotic signal and
osmosensing mechanism of an ABC transport system for glycine betaine. EMBO Journal, 20, 7022-7032.
2. Poolman, B., Blount, P., Folgering, J.,
Friesen, R.H.E., Moe, P.C., and Heide van der, T. (2002) How do membrane
proteins sense water stress? Molec. Microbiol., 44, 889-902.
-----------------------------------------------------------------------------------------------------------
Group name: Dept. of
Physiology
Location: Maastricht University
Web page:
E-Mail:
Jos.Heemskerk@fys.unimaas.nl
Phone: +31.43.3884003
Relevant research interests: (SEE BELOW)
Current system biology
activities:
SYSTEEMBIOLOGISCH ONDERZOEK VAN DE SPIERCEL
Het onderzoek
wordt uitgevoerd binnen een samenwerkingsproject van de capgroep Fysiologie,
CARIM, UM (prof.dr. G.J. van der Vusse) en de faculteit Electrotechniek TUE (dr.ir. N.A.W. van Riel en prof.dr.ir.
P.P.J. van den Bosch).
Het hoofddoel
van het project is om de energie- en calciumhuishouding in de hartspiercel
mathematisch te modelleren waarbij het model direct gekoppeld wordt aan
kwantitatieve experimentele gegevens. Dit resulteert in een modelgebaseerde
interpretatie van experimentele data. Hiertoe wordt gebruik gemaakt van Systeem
Theoretische principes waarbij onderscheid gemaakt wordt tussen massastromen en
informatie. De systeem biologische benadering richt zich op (relatief) compacte
beschrijvingen van het dynamisch gedrag door met name de (hiërarchische) regulatie
mechanismen te modelleren. Hierbij is kennisgedreven modelreductie van (te)
complexe fysiologische modellen essentieel. Er wordt gebruik gemaakt van model
analyse technieken zoals modale analyse en Metabolic Control Analysis. Vaak is
nog niet alle kwantitatieve informatie beschikbaar om te komen tot een
eenduidig model. Binnen de mogelijke modelrealisaties kan een specifiek model
geselecteerd worden op basis van additionele kennis in de vorm van
randvoorwaarden en (heterologe) experimentele data.
Onder normale
omstandigheden is de hartspier voor zijn energie-omzetting afhankelijk van
glucose en vetzuren als oxideerbare substraten. Deze substraten worden via de
bloedbaan aangevoerd en diffunderen via de endotheellijst en het interstitium
naar de cardiomyocyten. Na transport door het plasmamembraan en diffusie door
het cytoplasma vindt mitochondriale oxidatie plaats. De transportmechanismen
voor glucose (een hydrofiele verbinding) en vetzuur (sterk hydrofoob)
verschillen aanzienlijk. Vooral het mechanisme waarmee vetzuren door de
hartspier opgenomen en de wijze waarop de mitochondriale oxidatie geregeld
wordt is slechts in beperkte mate opgehelderd. Voorts blijkt uit recent
onderzoek dat tal van cardiale ziekten (hypertrofie/falen, diabetische cardiomyopathie)
gepaard gaan met veranderingen in de vetzuuroxidatie enerzijds en ophoping van
vetzuur anderzijds, hetgeen aanleiding kan zijn tot lipotoxiciteit.
Calcium ionen
in het cytoplasma van de cardiomyocyten spelen een essentiële rol bij de
mechanische activiteit van het hart. Rhytmische veranderingen in
cytoplasmatisch Ca2+ (laag tijdens diastole, hoog tijdens systole)
maken relaxatie en contractie van de myocyte mogelijk. Ook veranderingen in de
calcium homeostase blijken geassocieerd te zijn met tal van cardiomyopathieën.
Momenteel
worden mathematische modellen ontwikkeld en geimplementeerd om de in situ
kinetische eigenschappen van eiwitten die betrokken zijn bij het instandhouden
van de calcium huishouding en de cardiomyocyte te bepalen in het intacte hart
en te onderzoeken welke veranderingen opgetreden zijn in de kinetische
eigenschappen tijdens hartfalen en diabetische cardiomyopathie. Voorts worden mathematische modellen
ontworpen waarmee de opname, transport en oxidatie van vetzuur en glucose in de
hartspier wordt gesimuleerd en mogelijke barrières en controlepunten
geïdentificeerd en gekwantificeerd worden. Met deze modelmatige benadering zal
tevens getracht worden aan te geven in hoeverre veranderingen in het vetzuur-
en koolhydraatmetabolisme een causale rol spelen bij de functionele afname in
het falende en diabetische hart.
Tevens is het
doel om uiteindelijk tot een geïntegreerd model te komen van energiehuishouding
en calcium homeostase in de arbeidende cardiomyocyte.
Relevant collaborations:
-
Prof.dr.ir. P.P.J. van den Bosch en Dr.ir N.A.W. van Riel, Department of
Electrical Engineering, TU/e, NL
- Prof.dr. J.B. Bassingthwaighte, Center for Bioengineering, University
of Washington, Seattle, USA
- Dr. L. Ligeti, Dept. of Physiology, Semmelweis University, Budapest,
Hungary.
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Group name: Molecular Cell Physiology and Mathematical Biochemistry
Other staff members involved: Barbara Bakker (yeast, trypanosomes), Fred Boogerd (emergence), Klaas Krab (diabetes, modular
kinetic analyses), Wilfred Roling (microbial ecology), Jacky L. Snoep (als US,
South Africa; Silicon cell), Rob van Spanning (Paracoccus, gene networks and
rgeulation), Henk van Verseveld (microbial ecology)
Location: Centre for Research on BioComplex Systems, BCA, Free University and
Swammerdam Institute for Life Sciences, BCA, University of Amsterdam
Web page: http://www.bio.vu.nl/html/cell_phy.html
and <http://www.bio.vu.nl/hwconf>
E-Mail: hw@bio.vu.nl
Phone: +31 20 4447230 (+31 20 4447229
fax)
Relevant research interests:
-
System Biology: How through multiple
interactions macromolecules generate the functional behavior of living cells
-
Entering the living cell, i.e.
perform quantitative experiments to determine the behavior of macromolecules in
living cells
-
Principles of control, regulation
and non equilibrium thermodynamics and statistical mechanics
-
Silicon cell, i.e. computer replica
of parts of living cells
-
Network-based drug design
-
Ecological control analysis, i.e.
3exmaine whether control and regulation properties of intracellular pathways
also operate in ecosystems
-
Integrative and vertical genomics:
How genome, transcriptome, proteome, metabolome and physiome together and not
individually lead to functioning genomics.
-
Integrative bioinformatics
-
Tumor system biology
Current system biology activities:
Cellular
Bioinformatics, (including Theoretical
Biochemistry, Computational
biochemistry, and Mathematical Biochemistry, Mathematical Cell Biology, and
Quantitative
Biochemistry)
Relevant
collaborations (e.g.):
-
National:
·
Peletier, Blom, van Schuppen
(CWI)
·
Kaandorp (UvA)
·
Hellingwerf, Brul (UvA)
·
Jeneson (Utrecht)
·
Nicolay (Eindhoven)
·
Teusink (Wageningen)
-
International:
·
Heinrich (Berlin)
·
Snoep (Stellenbosch)
·
Kholodenko (Philadelphia)
Representative publications
(possibly links to pdf files):
http://www.bio.vu.nl/hwconf/papers
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Group leader: Bé Wieringa.
Group name: Department of Cell Biology, NCMLS UMCN.
Other Staff members: Jack
Fransen (UHD), Ineke van der Zee (UD), Frank Oerlemans (technician), Helma Pluk
(post-doc), Edwin Janssen (post-doc), Wieke de Bruin (post-doc), Jan Kuiper
(Ph.D.student), Femke Streijger (Ph.D.student).
Location: NCMLS
UMCN University Nijmegen.
Web page: www.ncmls.kun.nl
E.mail: b.wieringa@ncmls.kun.nl.
Phone: 31-24-3614329/3614287;
Fax: 31-24-3615317.
Relevant research interests:
The cellular energetics network for high-energy phosphoryl (i.e. mainly
ATP) transfer in mammalian cells consists of several redundant pathways, in
which several glycolytic enzymes, members of the creatine kinase (CK) and
adenylate kinase (AK) families of enzymes and nucleoside diphosphate kinases
(NDPK) play a determining role. Reactions in this complex network are highly
compartmentalized and require delicate coupling between cytosolic and
organellar events, with coordinated control of cytoarchitectural arrangements
and mitochondrial biogenesis and respiration, in a cell-type and
developmental-stage dependent manner. It has now been well established that the
individual enzymes in the ~P-transfer network work in close physical and
functional association with the systems for cell motility and contraction
(muscle, polarized migrating cells), intracellular transport and ion
homeostasis (muscle, neural cells) machinery. Moreover, the same network also
serves to protect cells against ischemic and anoxic stress and in providing
(cancer) cells with specially endowed survival skills.
During the past decade our group has been
employing reverse genetic approaches with gene knockout and pharmacological
inhibition in cellular and animal models to study the cellular effects of
intrinsic or extrinsic metabolic stress in the ~P transfer network in muscle,
brain and cancer cells. Our studies with cDNA arrays, semiquantitative Western
blotting, ~P flux measurements and physiological and behavioral analysis with
biochemical, cell biological, NMR/MRI procedures have revealed that every
pertubation in the large-scale organized energetics network (CK-AK knockout or
glycolytic enzyme impairment) results in a cell- and mutation-type dependent
multigene/multitranscript/mutiprotein response. Adaptation and remodeling
involved (i) regulation at the transcriptional and post-transcriptional level,
(ii) changes in the positioning and dynamics of the cytoarchitectural
organization, and (iii) rewiring of activity through redundant ~P transfer
pathways.
Current system biology activities:
Our present studies focus on the combined use of genomics-proteomics-and
metabolomics approaches to unravel the control of regulatory metabolic-status
signaling pathways (calcineurin-NFat, AMPK, mTOR and transcriptional
co-activator events) that sense the metabolic stress in the ~P transfer network
and contribute to the adaptational response. Moreover, we now concentrate on
the study of the molecular environment of CK, AK and glycolytic enzymes and the
use of quantitative real-time dynamic microscopy imaging methods to follow
metabolite (ion) and enzyme behavior, to better understand their role in
cellular energetics.
Relevant collaborations: Together with the group of dr. Peter Willems/W.Koopman (Dept. Biochemistry NCMLS, UMCN) we work on a computer modeling environment for quantitative description of changes in calcium-ion homeostasis, protein and organelle (mitochondrial)dynamics, and metabolite (NADH, ATP) distribution modes. At the international level we work together with dr. A.Terzic/P.Dzeja for ~P flux and physiological modeling.
Representative publications:
See www.ncmls.kun.nl dept. Cell
Biology for background info and movies.
1.
Deursen, J. van, Heerschap, A., Oerlemans, F.,
Ruitenbeek, W., Jap, P., Laak, H. ter, & Wieringa, B. (1993). Skeletal Muscles of
Mice Deficient in Muscle Creatine Kinase Lack Burst Activity. Cell, 74, 621-631.
2.
Deursen, J. van, Ruitenbeek, W., Heerschap, A.,
Jap, P., Laak, H. ter, & Wieringa, B (1994). Creatine kinase (CK) in
skeletal muscle energy metabolism: A study of mouse mutants with graded
reduction in muscle CK expression.
Proc.Natl.Acad Sci USA 91, 9091-9095.
3.
Steeghs, K., Benders, A., Oerlemans, F., de Haan,
A., Heerschap, A., Ruitenbeek, W., Jost, C., van Deursen, J., Perryman, B.,
Pette, D., Brückwilder, M., Koudijs, J., Jap, P., Veerkamp, J. and Wieringa. B. (1997) Altered
Ca2+ responses in muscles with combined mitochondrial and cytosolic
creatine kinase deficiencies. Cell 89, 93-103.
4.
Janssen, E., Dzeja,
P.P., Oerlemans, F., Simonetti, A.W., Heerschap, A., de Haan, A., Rush,
P.S., Terjung, R.R., Wieringa, B.and
Terzic, A. (2000) Adenylate kinase 1 gene deletion disrupts muscle energetic
economy despite metabolic rearrangement. EMBO
J. 19, 6371-6381.
5.
de Groof,AJ;
Oerlemans,FT; Jost,CR; Wieringa,B. Changes in glycolytic network and
mitochondrial design in creatine kinase-deficient muscles (2001) Muscle-Nerve.
24(9): 1188-96.
6.
Jost, C., van der Zee, C.E.E.M., in ’t Zandt, H.J.A.,
Oerlemans, F., Verheij, M., Streijger, F., Fransen, J., van Deursen, J.,
Heerschap, A., Cools, A. and Wieringa, B. (2002) Creatine kinase B-driven
energy transfer in the brain is important for habituation and spatial learning
behaviour, mossy fibre field size and determination of seizure susceptibility. Eur. J. Neurosci. 15, 1692-1706.
7.
Janssen, E., de Groof, A, Wijers M, Fransen, J.,
Dzeja P.P., Terzic A., and Wieringa, B. (2003). Adenylate kinase 1
deficiency induces molecular and structural adaptations to support muscle
energy metabolism. J.Biol.Chem. 278, in press.