2. Loughborough University
40 Research Institutes and Centers
23 academic departments
Systems Engineering department
Advanced Systems, Modeling and Simulation
Research Group
Development of better modeling and
simulation methodologies, but also application of
state of the art techniques to help understand and
predict the behavior of complex systems
3. Outline
Project Fallot
Heart Developement
Heart Disease
Multiscale Modelling
My project : the NFAT/VEGF pathway
VEGF / AA / NO / Ca pathway
Ca2+ / Calcinerin / NFAT pathway
DSCR1/NFAT pathway
Conclusion
4. Project Fallot
•In developed countries, heart defects have an
occurrence of 0.8% in neonates and are responsible for
about 10% of childhood mortality
•The tetralogy of Fallot is one of the most common form
of congenital heart disease
•Research group composed of
• Systems Engineers at Loughborough University, within the
Systems Modeling and Simulation Group
• Medical experts from the University of Rennes 1
5. Heart Development
Embryonic heart development is a complex process that occurs
between week 3 and 6 of gestation
They are 3 main processes in embryonic heart development:
fusion of the endocardial tubes
heart looping
wedging.
6. Heart Disease (1)
While heart looping is In the normal situation
taking place, the OFT should rotate
endocardial cushions about 150 degrees,
grow in the outflow clockwise
tract (OFT) But there are several
Different disease mechanisms that can
classifications disrupt this
correspond to remodeling of OFT
different degrees of
rotation
7. Heart Disease (2)
Tetralogy of Fallot
The classification of Double Outlet Right Ventricle
(DORV) overlaps with the tetralogy of Fallot with
rotation varying from about 90 to 140 degrees.
8. Heart Disease (3)
The tetralogy of Fallot is defined as:
an over-riding aorta - displaced further to the left
than it should be
pulmonary stenosis : a ventricular septal defect
right ventricle hypertrophy.
The point that Project Fallot is currently
investigating is the hypothesis that suggests that
the tetralogy is in fact a "monology" - the latter
three defects occurring as a consequence of the
first one.
9. Epithilelial to Mesenchymal
Transformation
EMT is an important process in cardiac
development and disease
This period has many contributions to
morphogenetic processes in the embryonic heart,
such as:
the growth the endocardial cushions in the
atrioventricular (AV) canal
The growth of the outflow tract (OFT)
10. Multiscale Modeling (1)
Although it is known which pathways are required for
EMT in cardiac cushion development, there is limited
detail on how these pathways function and interact
Computer modeling provides a means
to rapidly develop pathway models, based on what is
known
and run simulations to form hypotheses.
Different types of computational model are suitable for
different levels ofbiological scale
Biochemical reactions can be represented as
networks or ODEs
Then we can use models at one level of scale, to
pass information to models at another level of scale.
12. My project
Protein interaction : the NFAT/VEGF pathway
VEGF / AA / NO / Ca Axis
Ca2+ / Calcinerin / NFAT Axis
DSCR1/NFAT pathway
13. VEGF/NFAT pathway (1)
VEGF is a pleiotropic factor that regulates :
cell proliferation
vascular permeability
chemotaxis
survival in endothelial cells vasculogenesis
angiogenesis
In the developing embryo VEGF must be tightly
controlled during valve development
14. VEGF/NFAT pathway (2)
In the first stage, activated NFAT represses VEGF
gene expression
lower levels of VEGF
Permits the transformation and migration of
mesenchymal cells into the cardiac jelly
In the second phase, activated NFAT activates
VEGF gene expression
mesenchymal cell proliferation is stopped and
existing cells are induced to differentiate into valve
leaflet precursors
VEGF act as a trigger
16. Sum up
Heart Development
Heart Disease
Tetralogy of Fallot
EMT
Control of VEGF level
NFAT/VEGF pathway
VEGF / AA / NO / Ca Axis
Ca2+ / Calcinerin / NFAT Axis
DSCR1/NFAT Axis
17. My model
The model I'm willing to develop is divided into 3
parts
VEGF activates Calcium influx via Nitric Oxide (NO)
and Arachidonic Acid (AA)
Calcium influx promote NFAT in the nucleus
DSCR1 compete with NFAT to bind to calcineurin
And is using two different tools
Matlab ODE
System Biology Markup Language
within COPASI software
18. VEGF / AA / NO / Ca Axis (1)
VEGF binds to Tirosine Kinase Receptor (RTK)
RTK activate a series of intracellular events
leading to the release of Arachidonic Acid (AA)
and Nitric Oxide (NO)
Both intracellular messenger are able to activate
plasmamembrane calcium channels
19. VEGF / AA / NO / Ca Axis (2)
Extraction of the
Mathematical model
from Tubulogenesis
(formation of tubules
in epithelial or
endothelial cells)
20. VEGF / AA / NO / Ca Axis (3)
Using deterministic Focus on temporal
Ordinary Differential behaviour
Equations
31. Results
The behaviour seems to correspond to
publications
An objective would be to replace Ca’s simple
event input with experimental data or data from
VEGF/AA/NO/Ca Model
Another would be to perform more precise
analysis on initial concentrations/parameters
Another would be to perform positive feedback
with VEGF
32. DSCR1/NFAT interactions (1)
We just have seen the promotion of NFAT to the
nucleus
We have seen that once the NFAT is in the nucleus it
can activates VEGF
We have also seen that it can perform either positive
or negative feedback to control the VEGF activation.
In this section we will focus on the negative feedback
via the DSCR1 protein
DSCR1 has been shown to bind to calcineurin and to
inhibit its activity,
preventing the activation (dephosphorylation) of NFAT
and its translocation to the nucleus.
34. Perspectives
For now several model have been made
Need to put them together
Parameter analysis to improve the accuracy of
the model
RGB video processing to get experimental data
35. Conclusion
This is only a start
Great experience
As a biological engineer
As a research student
As a foreign student
36. References
Scianna, M., et al.
A multiscale hybrid approach for vasculogenesis and
related potential blocking therapies
Michael Vagner and M. A. Q. Siddiqui, Signal
Transduction in Early Heart Development (II)
Wayne g. Fisher, Pei-Chi Yang, Ram K. Medikonduri
and M. Saleet Jafri,
NFAT and NFKB Activation in T Lymphocytes : A
Model of Differential Activation of Gene Expression
Abdulla T., Imms R., Schleich J-M. and Summers R :
Multiscale Information Modelling for Heart
Morphogenesis