WntCellCycleOdeSystem.cpp

/*

Copyright (C) University of Oxford, 2005-2009

University of Oxford means the Chancellor, Masters and Scholars of the
University of Oxford, having an administrative office at Wellington
Square, Oxford OX1 2JD, UK.

This file is part of Chaste.

Chaste is free software: you can redistribute it and/or modify it
under the terms of the GNU Lesser General Public License as published
by the Free Software Foundation, either version 2.1 of the License, or
(at your option) any later version.

Chaste is distributed in the hope that it will be useful, but WITHOUT
ANY WARRANTY; without even the implied warranty of MERCHANTABILITY or
FITNESS FOR A PARTICULAR PURPOSE.  See the GNU Lesser General Public
License for more details. The offer of Chaste under the terms of the
License is subject to the License being interpreted in accordance with
English Law and subject to any action against the University of Oxford
being under the jurisdiction of the English Courts.

You should have received a copy of the GNU Lesser General Public License
along with Chaste. If not, see <http://www.gnu.org/licenses/>.

*/
#include "WntCellCycleOdeSystem.hpp"
#include "CellwiseOdeSystemInformation.hpp"

WntCellCycleOdeSystem::WntCellCycleOdeSystem(double WntLevel, const CellMutationState& rMutationState)
        : AbstractOdeSystem(9)
{
    mpSystemInfo.reset(new CellwiseOdeSystemInformation<WntCellCycleOdeSystem>);
    
    Init(); // set up parameter values

    double destruction_level = ma5d/(ma4d*WntLevel+ma5d);
    double beta_cat_level_1 = -1.0;
    double beta_cat_level_2 = -1.0;

    mMutationState = rMutationState;

    // These three lines set up a Wnt signalling pathway in a steady state
    if (mMutationState == HEALTHY || mMutationState == LABELLED)    // healthy cells
    {
        beta_cat_level_1 = 0.5*ma2d/(ma2d+ma3d*destruction_level);
        beta_cat_level_2 = 0.5*ma2d/(ma2d+ma3d*destruction_level);
    }
    else if (mMutationState == APC_ONE_HIT) // APC +/-
    {
        beta_cat_level_1 = 0.5*ma2d/(ma2d+0.5*ma3d*destruction_level); // only half are active
        beta_cat_level_2 = 0.5*ma2d/(ma2d+0.5*ma3d*destruction_level);
    }
    else if (mMutationState == BETA_CATENIN_ONE_HIT) // Beta-cat delta 45
    {
        beta_cat_level_1 = 0.5*ma2d/(ma2d+ma3d*destruction_level);
        beta_cat_level_2 = 0.5;
    }
    else if (mMutationState == APC_TWO_HIT) // APC -/-
    {
        destruction_level = 0.0; // no active destruction complex
        beta_cat_level_1 = 0.5; // fully active beta-catenin
        beta_cat_level_2 = 0.5; // fully active beta-catenin
    }
    else
    {
        // can't get here until new mutation states are added to CellMutationState
        NEVER_REACHED;
    }

    // Cell-specific initial conditions
    SetInitialConditionsComponent(5u, destruction_level);
    SetInitialConditionsComponent(6u, beta_cat_level_1);
    SetInitialConditionsComponent(7u, beta_cat_level_2);
    SetInitialConditionsComponent(8u, WntLevel);
}

void WntCellCycleOdeSystem::SetMutationState(const CellMutationState& rMutationState)
{
    mMutationState = rMutationState;
}

WntCellCycleOdeSystem::~WntCellCycleOdeSystem(void)
{
    // Do nothing
}

void WntCellCycleOdeSystem::Init()
{
    // Initialise model parameter values
    // Swat (2004) Parameters
    double k1 = 1.0;
    double k2 = 1.6;
    double k3 = 0.05;
    double k16 = 0.4;
    double k34 = 0.04;
    double k43 = 0.01;
    double k61 = 0.3;
    double k23 = 0.3;
    double a = 0.04;
    double J11 = 0.5;
    double J12 = 5.0;
    double J61 = 5.0;
    double J62 = 8.0;
    double J13 = 0.002;
    double J63 = 2.0;
    double Km1 = 0.5;
    double Km2 = 4.0;
    double Km4 = 0.3;
    double kp = 0.05;
    double phi_pRb = 0.005;
    double phi_E2F1 = 0.1;
    double phi_CycDi = 0.023;
    double phi_CycDa = 0.03;
    double phi_pRbp = 0.06;

    // Mirams et al. parameter values
    double a1 = 0.423;
    double a2 = 2.57e-4;
    double a3 = 1.72;
    double a4 = 10.0;
    double a5 = 0.5;
    double WntMax = 10.0;
    double mitogenic_factorF = 6.0e-4;
    double APC_Total = 0.02;

    // Non-dimensionalise...
    mk2d = k2/(Km2*phi_E2F1);
    mk3d = k3*a1*mitogenic_factorF/(Km4*phi_E2F1*a2);
    mk34d = k34/phi_E2F1;
    mk43d = k43/phi_E2F1;
    mk23d = k23*Km2/(Km4*phi_E2F1);
    mad = a/Km2;
    mJ11d = J11*phi_E2F1/k1;
    mJ12d = J12*phi_E2F1/k1;
    mJ13d = J13*phi_E2F1/k1;
    mJ61d = J61*phi_E2F1/k1;
    mJ62d = J62*phi_E2F1/k1;
    mJ63d = J63*phi_E2F1/k1;
    mKm1d = Km1/Km2;
    mkpd = kp/(Km2*phi_E2F1);
    mphi_r = phi_pRb/phi_E2F1;
    mphi_i = phi_CycDi/phi_E2F1;
    mphi_j = phi_CycDa/phi_E2F1;
    mphi_p = phi_pRbp/phi_E2F1;
    ma2d = a2/phi_E2F1;
    ma3d = a3*APC_Total/phi_E2F1;
    ma4d = a4*WntMax/phi_E2F1;
    ma5d = a5/phi_E2F1;
    mk16d = k16*Km4/phi_E2F1;
    mk61d = k61/phi_E2F1;
    mPhiE2F1 = phi_E2F1;
}

void WntCellCycleOdeSystem::EvaluateYDerivatives(double time, const std::vector<double> &rY, std::vector<double> &rDY)
{
    double r = rY[0];
    double e = rY[1];
    double i = rY[2];
    double j = rY[3];
    double p = rY[4];
    double c = rY[5];
    double b1 = rY[6];
    double b2 = rY[7];
    double WntLevel = rY[8];

    double dx1 = 0.0;
    double dx2 = 0.0;
    double dx3 = 0.0;
    double dx4 = 0.0;
    double dx5 = 0.0;
    double dx6 = 0.0;
    double dx7 = 0.0;
    double dx8 = 0.0;

    /*
     * The variables are
     * 1. r = pRb
     * 2. e = E2F1
     * 3. i = CycD (inactive)
     * 4. j = CycD (active)
     * 5. p = pRb-p
     * 6. c = APC (Active)
     * 7. b = Beta-Catenin
    */

    // Bit back-to-front, but work out the Wnt section first...

    // Mutations take effect by altering the level of beta-catenin
    if (mMutationState==HEALTHY || mMutationState==LABELLED)    // HEALTHY CELL
    {
        // da
        dx6 = ma5d*(1.0-c) - ma4d*WntLevel*c;
        // db
        dx7 = ma2d*(0.5-b1) - ma3d*b1*c;
        dx8 = ma2d*(0.5-b2) - ma3d*b2*c;
    }
    else if (mMutationState==APC_ONE_HIT) // APC +/-
    {
        dx6 = ma5d*(1.0-c) - ma4d*WntLevel*c;
        dx7 = ma2d*(0.5-b1) - 0.5*ma3d*b1*c;
        dx8 = ma2d*(0.5-b2) - 0.5*ma3d*b2*c;
    }
    else if (mMutationState==BETA_CATENIN_ONE_HIT) // Beta-Cat D45
    {
        dx6 = ma5d*(1.0-c) - ma4d*WntLevel*c;
        dx7 = ma2d*(0.5-b1) - ma3d*b1*c;
        dx8 = ma2d*(0.5-b2);
    }
    else if (mMutationState==APC_TWO_HIT) // APC -/-
    {
        dx6 = 0.0;
        dx7 = ma2d*(0.5-b1);
        dx8 = ma2d*(0.5-b2);
    }
    else
    {
        // Can't get here until new mutation states are added to CellMutationState
        NEVER_REACHED;
    }

    // Now the cell cycle stuff...

    // dr
    dx1 = e/(mKm1d+e)*mJ11d/(mJ11d+r)*mJ61d/(mJ61d+p) - mk16d*r*j+mk61d*p-mphi_r*r;
    // de
    dx2 = mkpd+mk2d*(mad*mad+e*e)/(1+e*e)*mJ12d/(mJ12d+r)*mJ62d/(mJ62d+p) - e;
    // di
    dx3 = mk3d*(b1+b2) + mk23d*e*mJ13d/(mJ13d+r)*mJ63d/(mJ63d+p) + mk43d*j - mk34d*i*j/(1+j) - mphi_i*i;
    // dj
    dx4 = mk34d*i*j/(1+j) - (mk43d+mphi_j)*j;
    // dp
    dx5 = mk16d*r*j - mk61d*p - mphi_p*p;

    double factor = mPhiE2F1*60.0;  // convert non-dimensional d/dt s to d/dt in hours

    rDY[0] = dx1*factor;
    rDY[1] = dx2*factor;
    rDY[2] = dx3*factor;
    rDY[3] = dx4*factor;
    rDY[4] = dx5*factor;
    rDY[5] = dx6*factor;
    rDY[6] = dx7*factor; // beta-cat allele 1
    rDY[7] = dx8*factor; // beta-cat allele 2
    rDY[8] = 0.0; // do not change the Wnt level
}

CellMutationState& WntCellCycleOdeSystem::rGetMutationState()
{
    return mMutationState;
}

bool WntCellCycleOdeSystem::CalculateStoppingEvent(double time, const std::vector<double> &rY)
{
    double r = rY[0];
    double e = rY[1];
    double p = rY[4];
    double dY1 = mkpd+mk2d*(mad*mad+e*e)/(1+e*e)*mJ12d/(mJ12d+r)*mJ62d/(mJ62d+p) - e;
    double factor = mPhiE2F1*60.0;  // Convert non-dimensional d/dt s to d/dt in hours.
    dY1 = dY1*factor;

    assert(!isnan(rY[1]));
    assert(!isnan(dY1));
    return (rY[1] > 1.0 && dY1 > 0.0);
}

double WntCellCycleOdeSystem::CalculateRootFunction(double time, const std::vector<double> &rY)
{
    return rY[1] - 1.0;
}


template<>
void CellwiseOdeSystemInformation<WntCellCycleOdeSystem>::Initialise(void)
{
    this->mVariableNames.push_back("pRb");
    this->mVariableUnits.push_back("non_dim");
    this->mInitialConditions.push_back(7.357000000000000e-01);

    this->mVariableNames.push_back("E2F1");
    this->mVariableUnits.push_back("non_dim");
    this->mInitialConditions.push_back(1.713000000000000e-01);

    this->mVariableNames.push_back("CycD_i");
    this->mVariableUnits.push_back("non_dim");
    this->mInitialConditions.push_back(6.900000000000001e-02);

    this->mVariableNames.push_back("CycD_a");
    this->mVariableUnits.push_back("non_dim");
    this->mInitialConditions.push_back(3.333333333333334e-03);

    this->mVariableNames.push_back("pRb_p");
    this->mVariableUnits.push_back("non_dim");
    this->mInitialConditions.push_back(1.000000000000000e-04);

    this->mVariableNames.push_back("APC");
    this->mVariableUnits.push_back("non_dim");
    this->mInitialConditions.push_back(NAN); // will be filled in later

    this->mVariableNames.push_back("Beta_Cat1");
    this->mVariableUnits.push_back("non_dim");
    this->mInitialConditions.push_back(NAN); // will be filled in later

    this->mVariableNames.push_back("Beta_Cat2");
    this->mVariableUnits.push_back("non_dim");
    this->mInitialConditions.push_back(NAN); // will be filled in later

    this->mVariableNames.push_back("Wnt");
    this->mVariableUnits.push_back("non_dim");
    this->mInitialConditions.push_back(NAN); // will be filled in later
    
    this->mInitialised = true;
}

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