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NFAT/VEGF Pathway, Griselle, Jocelyn

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NFAT/VEGF Pathway, Griselle, Jocelyn

  1. 1. Internship at Loughborough, Jocelyn Griselle Heart Development pathway Jocelyn Griselle
  2. 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. 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. 4. Project Fallot•In developed countries, heart defects have anoccurrence of 0.8% in neonates and are responsible forabout 10% of childhood mortality•The tetralogy of Fallot is one of the most common formof 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. 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. 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. 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. 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. 9. Epithilelial to MesenchymalTransformation 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. 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.
  11. 11. Multiscale Modeling (2)
  12. 12. My project Protein interaction : the NFAT/VEGF pathway VEGF / AA / NO / Ca Axis Ca2+ / Calcinerin / NFAT Axis DSCR1/NFAT pathway
  13. 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. 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
  15. 15. VEGF/NFAT pathway (3) This control is done via the NFAT/VEGF pathway
  16. 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. 17. My model The model Im 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. 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. 19. VEGF / AA / NO / Ca Axis (2) Extraction of the Mathematical model from Tubulogenesis (formation of tubules in epithelial or endothelial cells)
  20. 20. VEGF / AA / NO / Ca Axis (3) Using deterministic  Focus on temporal Ordinary Differential behaviour Equations
  21. 21. VEGF / AA / NO / Ca Axis (3)
  22. 22. Matlab Code
  23. 23. Results
  24. 24. Ca2+ / Calcinerin / NFAT Axis Ca2+ influx activates Calcineurin Calcinerin dephosphorylates NFAT Which promote NFAT translation into the nucleus Where it activates or represses target gene
  25. 25. Ca2+ / Calcinerin / NFAT Axis System Markup Biology Language (SBML) COPASI Software  Graphic Interface  Deterministic and stochastic simulations
  26. 26. Ca2+ / Calcinerin / NFAT Axis Model already done via SBML code, 4 stages  Calcium inflow to cell (cytosol)  Activation of calcinerium  Calcinerium + NFAT(P) calcineurin/NFAT(P) complex  Calcineurin/NFAT(P) complex calcineurin/NFAT nucl.
  27. 27. Calcium inflow to cell Input triggered by a simple event algorithm  Ca=1 umol/l for t=[0..10] and t=[100..110]
  28. 28. Activation of calcinerium
  29. 29. Calcinerium + NFAT(P)calcineurin/NFAT(P) complex
  30. 30. Calcineurin/NFAT(P) complexcalcineurin/NFAT nucl.
  31. 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. 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.
  33. 33. DSCR1/NFAT interactions (2)
  34. 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. 35. Conclusion This is only a start Great experience  As a biological engineer  As a research student  As a foreign student
  36. 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

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