Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Lotte Ramekers Research questions Introduction Models Methods Experiments and results Conclusions Questions How can the effects of the drug dofetilide on the electrical activation of the IKr channel in a rabbit ventricular myocyte be modelled? Research Questions ∙ Introduction ∙ Models ∙ Methods ∙ Experiments ∙ Conclusions ∙ Questions 2 How can the behavioural kinetics and block of an IKr channel be modelled? How can an IKr channel model be used to simulate the electrical activation? What are the advantages and disadvantages of the different model structures? Research Questions ∙ Introduction ∙ Models ∙ Methods ∙ Experiments ∙ Conclusions ∙ Questions 2 Introduction Research Questions ∙ Introduction ∙ Models ∙ Methods ∙ Experiments ∙ Conclusions ∙ Questions How can the effects of the drug dofetilide on the electrical activation of the IKr channel in a rabbit ventricular myocyte be modelled? Open The IKr channel… Is an ion channel Transports potassium (K+) ions through the heart cell membrane Has 3 distinct states: Open, closed and incativated Closed Research Questions ∙ Introduction ∙ Models ∙ Methods ∙ Experiments ∙ Conclusions ∙ Questions Inactivated 3 How can the effects of the drug dofetilide on the electrical activation of the IKr channel in a rabbit ventricular myocyte be modelled? Equilibrium + -+ + - - + + + chemical gradient + + - + - + + + + - - + - + chemical gradient chemical gradient electrical gradient electrical gradient Research Questions ∙ Introduction ∙ Models ∙ Methods ∙ Experiments ∙ Conclusions ∙ Questions 2 How can the effects of the drug dofetilide on the electrical activation of the IKr channel in a rabbit ventricular myocyte be modelled? The chemical and electrical gradient affect all ion types This results in a constant flow of ions in and out of the heart cells Establishing the action potential (AP) Deficiencies in IKr channel: decreased repolarisation Research Questions ∙ Introduction ∙ Models ∙ Methods ∙ Experiments ∙ Conclusions ∙ Questions 5 How can the effects of the drug dofetilide on the electrical activation of the IKr channel in a rabbit ventricular myocyte be modelled? Regular IKr channel deficiency LQT2 Research Questions ∙ Introduction ∙ Models ∙ Methods ∙ Experiments ∙ Conclusions ∙ Questions 5 How can the effects of the drug dofetilide on the electrical activation of the IKr channel in a rabbit ventricular myocyte be modelled? Torsades de Pointes Ventricular Fibrillation Research Questions ∙ Introduction ∙ Models ∙ Methods ∙ Experiments ∙ Conclusions ∙ Questions 5 How can the behavioural kinetics and block of an IKr channel be modelled? Research Questions ∙ Introduction ∙ Models ∙ Methods ∙ Experiments ∙ Conclusions ∙ Questions Based on the model by C. Clancy and Y. Rudy Extend to incorporate block Based on approach of C. Clancy, Z. Zhu and Y. Rudy ? Research Questions ∙ Introduction ∙ Models ∙ Methods ∙ Experiments ∙ Conclusions ∙ Questions 9 αb = γα ∙ [Dof] βb = γβ Research Questions ∙ Introduction ∙ Models ∙ Methods ∙ Experiments ∙ Conclusions ∙ Questions 11 The possibility that a dofetilide molecule binds, depends on the physical shape of the ion channel The shape is altered by drug binding Research Questions ∙ Introduction ∙ Models ∙ Methods ∙ Experiments ∙ Conclusions ∙ Questions 11 αb = γα ∙ [Dof] δ βb = γβ Research Questions ∙ Introduction ∙ Models ∙ Methods ∙ Experiments ∙ Conclusions ∙ Questions 11 Suggested by E. Carmeliet αbr = γαbr ∙ [Dof] βbr = γβbr αbs = γαbs ∙ [Dof] βbs = γβbs Research Questions ∙ Introduction ∙ Models ∙ Methods ∙ Experiments ∙ Conclusions ∙ Questions 12 How can an IKr channel model be used to simulate the electrical activation? Research Questions ∙ Introduction ∙ Models ∙ Methods ∙ Experiments ∙ Conclusions ∙ Questions Experimental setting Isolate a ventricular cell Add electrodes (voltage clamp) Apply voltages according to a voltage clamp protocol Analyse the effects Research Questions ∙ Introduction ∙ Models ∙ Methods ∙ Experiments ∙ Conclusions ∙ Questions 12 Given: The transition rates The voltage clamp protocol We can calculate the fraction of ion channels per state Research Questions ∙ Introduction ∙ Models ∙ Methods ∙ Experiments ∙ Conclusions ∙ Questions 12 X: fraction of ion channels per state R(θ): matrix with transition rates First order Markov property: Change in channel occupancy is determined solely by the current state and the incoming and outgoing transition rates dX/dt = T(θ) ∙ X, with T(θ) = RT(θ) – diag(R(θ) ∙ 1) Voltage is clamped: T(θ) is constant for every voltage step Conservation of channels: 1T ∙ T(θ) = 0 Sum of fractions: ∑ Xi = 1 Steady state occupancy X is given by: T(θ) 1 ∙ ∙ ∙1 X = [ 0 ∙ ∙ ∙ 0 1 ]T Research Questions ∙ Introduction ∙ Models ∙ Methods ∙ Experiments ∙ Conclusions ∙ Questions 13 Change in channel occupancy: dX/dt = T(θ) ∙ X with T(θ) = RT(θ) – diag(R(θ) ∙ 1) General solution: X(t) = eT(θ)t ∙ X0 Involves the matrix exponent Using spectral decomposition: X(t) = ∑ αi ui eλit No longer involves the matrix exponent Research Questions ∙ Introduction ∙ Models ∙ Methods ∙ Experiments ∙ Conclusions ∙ Questions 14 Determine fraction of channels per state… in the Steady State (corresponding with v1) at the end of voltage step 2 (corresponding with v2) in last voltage step (corresponding with v3) Tail current is given by: IKr = (V - EKr) ∙ GKr ∙ O V: membrane potential Ekr : equilibrium potential GKr: cell conductance O: fraction of ion channels in open state Research Questions ∙ Introduction ∙ Models ∙ Methods ∙ Experiments ∙ Conclusions ∙ Questions 14 Three Markov models The Simple Model The Cooperative Binding Model The 2-Phase Model The corresponding transition rates can be used to calculate the tail current The maximum tail current can be compared to experimental data to test the model performance Research Questions ∙ Introduction ∙ Models ∙ Methods ∙ Experiments ∙ Conclusions ∙ Questions 14 What are the advantages and disadvantages of the different model structures? Research Questions ∙ Introduction ∙ Models ∙ Methods ∙ Experiments ∙ Conclusions ∙ Questions Experiments performed by E. Carmeliet On a rabbit ventricular myocyte Using the portrayed voltage protocol Applying different doses of dofetilide Research Questions ∙ Introduction ∙ Models ∙ Methods ∙ Experiments ∙ Conclusions ∙ Questions 17 Activation Curve 0 M Dof. at +10 mV scaled to 100% Concentration Response Curve 0 M Dof. scaled to 100%, measured at 0 mV Research Questions ∙ Introduction ∙ Models ∙ Methods ∙ Experiments ∙ Conclusions ∙ Questions 17 Create an initial population Evaluate the individual performances Populate the next generation Determine individuals that are allowed to reproduce (using Tournament Selection) Create offspring, based on parent’s parameters Randomly mutate parameter values Repeat process… Research Questions Introduction ∙ Models ∙ Methods ∙ Experiments ∙ Conclusions ∙ Questions 18 Simple Model Cooperative Binding Model Research Questions ∙ Introduction ∙ Models ∙ Methods ∙ Experiments ∙ Conclusions ∙ Questions 2-Phase Model 24 Two types of experiments Effect of various noise functions Effect of various number of affected parameters General form for noise functions Pnew, i = (1 + r ∙ s) ∙ Pi Pnew, i : new (altered) parameter Pi : original parameter r: random value drawn from normal distribution (µ = 0, σ = 1) s: relative standard deviation Research Questions ∙ Introduction ∙ Models ∙ Methods ∙ Experiments ∙ Conclusions ∙ Questions 25 Noise is added to all parameters Amount of noise is varied by varying s Error without adding noise is scaled to 1 Research Questions ∙ Introduction ∙ Models ∙ Methods ∙ Experiments ∙ Conclusions ∙ Questions 25 Noise function with s = 0.1 Number of altered parameters is varied Error without adding noise is scaled to 1 Research Questions ∙ Introduction ∙ Models ∙ Methods ∙ Experiments ∙ Conclusions ∙ Questions 26 How can the effects of the drug dofetilide on the electrical activation of the IKr channel in a rabbit ventricular myocyte be modelled? Research Questions ∙ Introduction ∙ Models ∙ Methods ∙ Experiments ∙ Conclusions ∙ Questions Model fit and sensitivity analysis: 2-Phase Model is best Cooperative Binding and 2-Phase Model produce similar output Most importantly: The research provides a general approach for modelling the effects of drug induced blockage on the electrical activation of ion channels Research Questions ∙ Introduction ∙ Models ∙ Methods ∙ Experiments ∙ Conclusions ∙ Questions 29 Implement more IKr channel models Incorporate the model into Puglisi and Bers’s rabbit ventricular action potential model Extend the theoretical analysis of Markov models for ion channels Research Questions ∙ Introduction ∙ Models ∙ Methods ∙ Experiments ∙ Conclusions ∙ Questions 31