Chaste Commit::ca8ccdedf819b6e02855bc0e8e6f50bdecbc5208
VanLeeuwen2009WntSwatCellCycleOdeSystem.cpp
1/*
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34*/
35
36#include "VanLeeuwen2009WntSwatCellCycleOdeSystem.hpp"
37#include "CellwiseOdeSystemInformation.hpp"
38#include "ApcOneHitCellMutationState.hpp"
39#include "ApcTwoHitCellMutationState.hpp"
40#include "BetaCateninOneHitCellMutationState.hpp"
41
43 double wntLevel,
44 boost::shared_ptr<AbstractCellMutationState> pMutationState,
45 std::vector<double> stateVariables)
47 mpMutationState(pMutationState),
48 mHypothesis(hypothesis),
49 mWntLevel(wntLevel)
50{
51 if (hypothesis!=1 && hypothesis!=2)
52 {
53 EXCEPTION("You must set up this cell cycle ODE system with hypothesis one or two.");
54 }
55
57
84 Init(); // set up parameter values
85
86 double d_d_hat = mDd + mXiD*wntLevel;
87 double d_d_x_hat = mDdx + mXiDx*wntLevel;
88 double d_x_hat = mDx + mXiX*wntLevel;
89 double p_c_hat = mPc + mXiC*wntLevel;
90
91 double sigma_D = 0.0; // for healthy cells
92 //double sigma_B = 0.0; // for healthy cells - never used!
93
94 if (!mpMutationState)
95 {
96 // No mutations specified
97 }
99 {
100 sigma_D = 0.5;
101 }
103 {
104 sigma_D = 1.0;
105 }
107 {
108 //sigma_B = 0.5; // never used!
109 }
110 // Other mutations have no effect.
111
112 // Cell-specific initial conditions
113 double steady_D = ((1.0-sigma_D)*mSd*mSx)/((1.0-sigma_D)*mSd*d_d_hat + d_x_hat*(d_d_hat + d_d_x_hat));
114 SetDefaultInitialCondition(5, steady_D); // Destruction complex (APC/Axin/GSK3B)
115
116 double temp = (mSx*(d_d_hat+d_d_x_hat))/((1.0-sigma_D)*mSd*d_d_hat+d_x_hat*(d_d_hat+d_d_x_hat));
117 SetDefaultInitialCondition(6, temp); // Axin
118
119 double steady_Cf = ((mSc-mDc*mKd - mPu*steady_D)+sqrt(SmallPow((mSc-mDc*mKd - mPu*steady_D),2) + (4.0*mSc*mDc*mKd)))/(2.0*mDc);
120 temp = (mPu*steady_D*steady_Cf)/(mDu*(steady_Cf+mKd));
121 SetDefaultInitialCondition(7, temp); // beta-catenin to be ubiquitinated
122
123 double theta = mDc + (mPu*steady_D)/(steady_Cf + mKd);
124
125 double steady_Co = ( mSc - p_c_hat - theta*mKc + sqrt(4.0*mSc*theta*mKc + SmallPow((mSc - p_c_hat - theta*mKc),2)) )/(2.0*theta);
126 SetDefaultInitialCondition(8, steady_Co); // Open form beta-catenin
127
128 double steady_Cc = steady_Cf - steady_Co;
129
130 if ((steady_Cc < 0) && (steady_Cc+100*DBL_EPSILON > 0) ) // stop protein values going -ve
131 {
132 steady_Cc = 0.0;
133 }
134 SetDefaultInitialCondition(9, steady_Cc); // Closed form beta-catenin
135
136 SetDefaultInitialCondition(12, mSa/mDa); // 'Free' adhesion molecules
137
138 SetDefaultInitialCondition(13, mSa*mSca*steady_Co/(mDa*mDca)); // Co-A Adhesion complex
139
140 SetDefaultInitialCondition(15, mSt/mDt); // `Free' transcription molecules (TCF)
141
142 SetDefaultInitialCondition(16, mSct*mSt*steady_Co/(mDt*mDct)); // Co-T open form beta-catenin/TCF
143
144 SetDefaultInitialCondition(17, mSct*mSt*steady_Cc/(mDt*mDct)); // Cc-T closed beta-catenin/TCF
145
146 temp = (mSct*mSt*mSy*steady_Cf)/(mDy*(mSct*mSt*steady_Cf + mDct*mDt*mKt));
147 SetDefaultInitialCondition(20, temp); // Wnt target protein
148
149 SetDefaultInitialCondition(21, wntLevel); // Wnt stimulus
150
151 if (stateVariables != std::vector<double>())
152 {
153 SetStateVariables(stateVariables);
154 }
155}
156
157void VanLeeuwen2009WntSwatCellCycleOdeSystem::SetMutationState(boost::shared_ptr<AbstractCellMutationState> pMutationState)
158{
159 mpMutationState = pMutationState;
160}
161
166
168{
169 // Swat (2004) parameters
170 double k1 = 1.0;
171 double k2 = 1.6;
172 double k3 = 0.05;
173 double k16 = 0.4;
174 double k34 = 0.04;
175 double k43 = 0.01;
176 double k61 = 0.3;
177 double k23 = 0.3;
178 double a = 0.04;
179 double J11 = 0.5;
180 double J12 = 5.0;
181 double J61 = 5.0;
182 double J62 = 8.0;
183 double J13 = 0.002;
184 double J63 = 2.0;
185 double Km1 = 0.5;
186 double Km2 = 4.0;
187 double Km4 = 0.3;
188 double kp = 0.05;
189 double phi_pRb = 0.005;
190 double phi_E2F1 = 0.1;
191 double phi_CycDi = 0.023;
192 double phi_CycDa = 0.03;
193 double phi_pRbp = 0.06;
194
195 // Value of the mitogenic factor to make the van Leeuwen model influence cell cycle just the same
196 double mitogenic_factorF = 1.0/25.0;
197
198 // Non-dimensionalise parameters
199 mk2d = k2/(Km2*phi_E2F1);
200 mk3d = k3*mitogenic_factorF/(Km4*phi_E2F1);
201 mk34d = k34/phi_E2F1;
202 mk43d = k43/phi_E2F1;
203 mk23d = k23*Km2/(Km4*phi_E2F1);
204 mad = a/Km2;
205 mJ11d = J11*phi_E2F1/k1;
206 mJ12d = J12*phi_E2F1/k1;
207 mJ13d = J13*phi_E2F1/k1;
208 mJ61d = J61*phi_E2F1/k1;
209 mJ62d = J62*phi_E2F1/k1;
210 mJ63d = J63*phi_E2F1/k1;
211 mKm1d = Km1/Km2;
212 mkpd = kp/(Km2*phi_E2F1);
213 mphi_r = phi_pRb/phi_E2F1;
214 mphi_i = phi_CycDi/phi_E2F1;
215 mphi_j = phi_CycDa/phi_E2F1;
216 mphi_p = phi_pRbp/phi_E2F1;
217 mk16d = k16*Km4/phi_E2F1;
218 mk61d = k61/phi_E2F1;
219 mPhiE2F1 = phi_E2F1;
220
221 // Initialize van Leeuwen model parameters
222 mSa = 20; // nM/h
223 mSca = 250; // (nMh)^-1
224 mSc = 25; // nM/h
225 mSct = 30; // (nMh)^-1
226 mSd = 100; // h^-1
227 mSt = 10; // nM/h
228 mSx = 10; // nM/h
229 mSy = 10; // h^-1
230 mDa = 2; // h^-1
231 mDca = 350; // h^-1
232 mDc = 1; // h^-1
233 mDct = 750; // h^-1
234 mDd = 5; // h^-1
235 mDdx = 5; // h^-1
236 mDt = 0.4; // h^-1
237 mDu = 50; // h^-1
238 mDx = 100; // h^-1
239 mDy = 1; // h^-1
240 mKc = 200; // nM
241 mKd = 5; // nM
242 mKt = 50; // nM
243 mPc = 0.0; // h^-1
244 mPu = 100; // h^-1
245 mXiD = 5; // h^-1
246 mXiDx = 5; // h^-1
247 mXiX = 200; // h^-1
248 if (mHypothesis==1)
249 {
250 mXiC = 0.0; // h^-1 (FOR HYPOTHESIS ONE)
251 }
252 else
253 {
254 mXiC = 5000.0; // h^-1 (FOR HYPOTHESIS TWO)
255 }
256}
257
258void VanLeeuwen2009WntSwatCellCycleOdeSystem::EvaluateYDerivatives(double time, const std::vector<double>& rY, std::vector<double>& rDY)
259{
260 double r = rY[0];
261 double e = rY[1];
262 double i = rY[2];
263 double j = rY[3];
264 double p = rY[4];
265
266 double dx1 = 0.0;
267 double dx2 = 0.0;
268 double dx3 = 0.0;
269 double dx4 = 0.0;
270 double dx5 = 0.0;
271
272 // Bit back-to-front, but work out the Wnt section first...
273
274 // Variables
275 double D = rY[5];
276 double X = rY[6];
277 double Cu = rY[7];
278 double Co = rY[8];
279 double Cc = rY[9];
280 double Mo = rY[10];
281 double Mc = rY[11];
282 double A = rY[12];
283 double Ca = rY[13];
284 double Ma = rY[14];
285 double T = rY[15];
286 double Cot = rY[16];
287 double Cct = rY[17];
288 double Mot = rY[18];
289 double Mct = rY[19];
290 double Y = rY[20];
291 double stimulus_wnt = rY[21];
292
293 // Totals
294 double Cf = Cc+Co;
295 double Ct = Cct+Cot;
296 double Mf = Mc+Mo;
297 double Mt = Mct+Mot;
298
299 double d_d_hat = mDd + mXiD*stimulus_wnt;
300 double d_d_x_hat = mDdx + mXiDx*stimulus_wnt;
301 double d_x_hat = mDx + mXiX*stimulus_wnt;
302 double p_c_hat = mPc + mXiC*stimulus_wnt;
303
304 double sigma_D = 0.0; // for healthy cells
305 double sigma_B = 0.0; // for healthy cells
306
307 if (!mpMutationState)
308 {
309 // No mutations specified
310 }
312 {
313 sigma_D = 0.5;
314 }
316 {
317 sigma_D = 1.0;
318 }
320 {
321 sigma_B = 0.5;
322 }
323 // Other mutations have no effect.
324
325 // Now the cell cycle stuff...
326
327 // dr
328 dx1 = e/(mKm1d+e)*mJ11d/(mJ11d+r)*mJ61d/(mJ61d+p) - mk16d*r*j+mk61d*p-mphi_r*r;
329 // de
330 dx2 = mkpd+mk2d*(mad*mad+e*e)/(1+e*e)*mJ12d/(mJ12d+r)*mJ62d/(mJ62d+p) - e;
331 // di - changed to include Ct+Mt - transcriptional beta-catenin
332 dx3 = mk3d*(Ct+Mt) + mk23d*e*mJ13d/(mJ13d+r)*mJ63d/(mJ63d+p) + mk43d*j - mk34d*i*j/(1+j) - mphi_i*i;
333 // dj
334 dx4 = mk34d*i*j/(1+j) - (mk43d+mphi_j)*j;
335 // dp
336 dx5 = mk16d*r*j - mk61d*p - mphi_p*p;
337
338 double factor = mPhiE2F1*60.0; // Convert non-dimensional d/dt s to d/dt in hours.
339
340 rDY[0] = dx1*factor;
341 rDY[1] = dx2*factor;
342 rDY[2] = dx3*factor;
343 rDY[3] = dx4*factor;
344 rDY[4] = dx5*factor;
345
346 // The van Leeuwen ODE system
347 rDY[5] = (1.0-sigma_D)*mSd*X - (d_d_hat + d_d_x_hat)*D;
348 rDY[6] = mSx - (1.0-sigma_D)*mSd*X - d_x_hat*X + d_d_x_hat*D;
349 rDY[7] = (mPu*D*Cf)/(Cf+mKd) - mDu*Cu;
350
351 rDY[8] = (1.0-sigma_B)*mSc + mDca*Ca + mDct*Cot - (mSca*A + mSct*T + mDc)*Co
352 - (p_c_hat*Co)/(Co + Mo + mKc) - (mPu*D*Co)/(Cf+mKd);
353
354 rDY[9] = (p_c_hat*Co)/(Co + Mo + mKc) + mDct*Cct - (mSct*T + mDc)*Cc
355 - (mPu*D*Cc)/(Cf+mKd);
356
357 rDY[10] = sigma_B*mSc + mDca*Ma + mDct*Mot - (mSca*A + mSct*T + mDc)*Mo
358 - (p_c_hat*Mo)/(Co + Mo + mKc);
359
360 rDY[11] = (p_c_hat*Mo)/(Co + Mo + mKc) + mDct*Mct - (mSct*T + mDc)*Mc;
361 rDY[12] = mSa + mDca*(Ca+Ma) - (mSca*(Co+Mo) + mDa)*A;
362 rDY[13] = mSca*Co*A - mDca*Ca;
363 rDY[14] = mSca*Mo*A - mDca*Ma;
364 rDY[15] = mSt + mDct*(Ct+Mt) - mSct*(Cf+Mf)*T - mDt*T;
365 rDY[16] = mSct*Co*T - mDct*Cot;
366 rDY[17] = mSct*Cc*T - mDct*Cct;
367 rDY[18] = mSct*Mo*T - mDct*Mot;
368 rDY[19] = mSct*Mc*T - mDct*Mct;
369 rDY[20] = (mSy*(Ct+Mt))/(Ct + Mt + mKt) - mDy*Y;
370 rDY[21] = 0.0; // don't interfere with Wnt stimulus
371}
372
373const boost::shared_ptr<AbstractCellMutationState> VanLeeuwen2009WntSwatCellCycleOdeSystem::GetMutationState() const
374{
375 return mpMutationState;
376}
377
378bool VanLeeuwen2009WntSwatCellCycleOdeSystem::CalculateStoppingEvent(double time, const std::vector<double>& rY)
379{
380 std::vector<double> dy(rY.size());
381 EvaluateYDerivatives(time, rY, dy);
382
383 return (rY[1] > 1.0 && dy[1] > 0.0);
384}
385
386double VanLeeuwen2009WntSwatCellCycleOdeSystem::CalculateRootFunction(double time, const std::vector<double>& rY)
387{
388 return rY[1] - 1.0;
389}
390
391template<>
393{
394 this->mVariableNames.push_back("pRb");
395 this->mVariableUnits.push_back("non_dim");
396 this->mInitialConditions.push_back(7.357000000000000e-01);
397
398 this->mVariableNames.push_back("E2F1");
399 this->mVariableUnits.push_back("non_dim");
400 this->mInitialConditions.push_back(1.713000000000000e-01);
401
402 this->mVariableNames.push_back("CycD_i");
403 this->mVariableUnits.push_back("non_dim");
404 this->mInitialConditions.push_back(6.900000000000001e-02);
405
406 this->mVariableNames.push_back("CycD_a");
407 this->mVariableUnits.push_back("non_dim");
408 this->mInitialConditions.push_back(3.333333333333334e-03);
409
410 this->mVariableNames.push_back("pRb_p");
411 this->mVariableUnits.push_back("non_dim");
412 this->mInitialConditions.push_back(1.000000000000000e-04);
413
414 this->mVariableNames.push_back("D"); // Destruction complex (APC/Axin/GSK3B)
415 this->mVariableUnits.push_back("nM");
416 this->mInitialConditions.push_back(NAN); // will be filled in later
417
418 this->mVariableNames.push_back("X"); // Axin
419 this->mVariableUnits.push_back("nM");
420 this->mInitialConditions.push_back(NAN); // will be filled in later
421
422 this->mVariableNames.push_back("Cu"); // beta-catenin to be ubiquitinated
423 this->mVariableUnits.push_back("nM");
424 this->mInitialConditions.push_back(NAN); // will be filled in later
425
426 this->mVariableNames.push_back("Co"); // Open form beta-catenin
427 this->mVariableUnits.push_back("nM");
428 this->mInitialConditions.push_back(NAN); // will be filled in later
429
430 this->mVariableNames.push_back("Cc"); // Closed form beta-catenin
431 this->mVariableUnits.push_back("nM");
432 this->mInitialConditions.push_back(NAN); // will be filled in later
433
434 this->mVariableNames.push_back("Mo"); // Open form mutant beta-catenin
435 this->mVariableUnits.push_back("nM");
436 this->mInitialConditions.push_back(0.0);
437
438 this->mVariableNames.push_back("Mc"); // Closed form mutant beta-catenin
439 this->mVariableUnits.push_back("nM");
440 this->mInitialConditions.push_back(0.0);
441
442 this->mVariableNames.push_back("A"); // 'Free' adhesion molecules
443 this->mVariableUnits.push_back("nM");
444 this->mInitialConditions.push_back(NAN); // will be filled in later
445
446 this->mVariableNames.push_back("Ca"); // Co-A Adhesion complex
447 this->mVariableUnits.push_back("nM");
448 this->mInitialConditions.push_back(NAN); // will be filled in later
449
450 this->mVariableNames.push_back("Ma"); // Mo-A Mutant adhesion complex
451 this->mVariableUnits.push_back("nM");
452 this->mInitialConditions.push_back(0.0);
453
454 this->mVariableNames.push_back("T"); // `Free' transcription molecules (TCF)
455 this->mVariableUnits.push_back("nM");
456 this->mInitialConditions.push_back(NAN); // will be filled in later
457
458 this->mVariableNames.push_back("Cot"); // Co-T open form beta-catenin/TCF
459 this->mVariableUnits.push_back("nM");
460 this->mInitialConditions.push_back(NAN); // will be filled in later
461
462 this->mVariableNames.push_back("Cct"); // Cc-T closed beta-catenin/TCF
463 this->mVariableUnits.push_back("nM");
464 this->mInitialConditions.push_back(NAN); // will be filled in later
465
466 this->mVariableNames.push_back("Mot"); // Mo-T open form mutant beta-catenin/TCF
467 this->mVariableUnits.push_back("nM");
468 this->mInitialConditions.push_back(0.0);
469
470 this->mVariableNames.push_back("Mct"); // Mc-T closed form mutant beta-catenin/TCF
471 this->mVariableUnits.push_back("nM");
472 this->mInitialConditions.push_back(0.0);
473
474 this->mVariableNames.push_back("Y"); // Wnt target protein
475 this->mVariableUnits.push_back("nM");
476 this->mInitialConditions.push_back(NAN); // will be filled in later
477
478 this->mVariableNames.push_back("Sw"); // Wnt stimulus
479 this->mVariableUnits.push_back("nM");
480 this->mInitialConditions.push_back(NAN); // will be filled in later
481
482 this->mInitialised = true;
483}
484
489
494
495// Serialization for Boost >= 1.36
#define EXCEPTION(message)
#define CHASTE_CLASS_EXPORT(T)
void SetStateVariables(const std::vector< double > &rStateVariables)
void SetDefaultInitialCondition(unsigned index, double initialCondition)
boost::shared_ptr< AbstractOdeSystemInformation > mpSystemInfo
const boost::shared_ptr< AbstractCellMutationState > GetMutationState() const
double CalculateRootFunction(double time, const std::vector< double > &rY)
bool CalculateStoppingEvent(double time, const std::vector< double > &rY)
void EvaluateYDerivatives(double time, const std::vector< double > &rY, std::vector< double > &rDY)
void SetMutationState(boost::shared_ptr< AbstractCellMutationState > pMutationState)
boost::shared_ptr< AbstractCellMutationState > mpMutationState
VanLeeuwen2009WntSwatCellCycleOdeSystem(unsigned hypothesis, double wntLevel=0.0, boost::shared_ptr< AbstractCellMutationState > pMutationState=boost::shared_ptr< AbstractCellMutationState >(), std::vector< double > stateVariables=std::vector< double >())