JWS Online

leloup3

leloup3

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Reactions

reaction_0

Mb synthesized

∅ > species_0

reaction_1

Mb translated into protein

∅ > species_1

reaction_10

Mp translated into protein

∅ > species_8

reaction_11

Pcp specific degradation

species_9 > ∅

reaction_12

Pc phospholation

species_8 > species_9

reaction_13

Cc and Pc produce PCc

species_4 + species_8 = species_10

reaction_14

PCc phospholation

species_10 > species_11

reaction_15

PCcp specific degradation

species_11 > ∅

reaction_16

PCc transfered into nuclear

species_10 = species_12

reaction_17

PCnp nonspecific degradation

species_14 > ∅

reaction_18

Bcp nonspecific degradation

species_2 > ∅

reaction_19

Bnp nonspecific degradation

species_13 > ∅

reaction_2

Mb nonspecific degradation

species_0 > ∅

reaction_20

Mc synthesis

∅ > species_5

reaction_21

PCn phospholation

species_12 > species_14

reaction_22

Mp nonspecific degradation

species_7 > ∅

reaction_23

Per_Cry and Clock_Bmal form inactive complex

species_12 + species_3 = species_15

reaction_24

Mb specific degradation

species_0 > ∅

reaction_25

Mc specific degradation

species_5 > ∅

reaction_26

Mp specific degradation

species_7 > ∅

reaction_27

Pc nonspecific degradation

species_8 > ∅

reaction_28

Cc nonspecific degradation

species_4 > ∅

reaction_29

Pcp nonspecific degradation

species_9 > ∅

reaction_3

Bc phosphorylation

species_1 > species_2

reaction_30

Ccp nonspecific degradation

species_6 > ∅

reaction_31

PCcp nonspecific degradation

species_11 > ∅

reaction_32

PCc nonspecific degradation

species_10 > ∅

reaction_33

PCnp specific degradation

species_14 > ∅

reaction_34

Bc nonspecific degradation

species_1 > ∅

reaction_35

Bcp specific degradation

species_2 > ∅

reaction_36

Bn phospholation

species_3 > species_13

reaction_37

Bnp specific degradation

species_13 > ∅

reaction_38

In nonspecific degration

species_15 > ∅

reaction_39

In specific degradation

species_15 > ∅

reaction_4

Bc transfered from cytosolic to nuclear

species_1 = species_3

reaction_40

Bn nonspecific degradation

species_3 > ∅

reaction_41

Bcp dephospholation

species_2 > species_1

reaction_42

Bnp dephospholation

species_13 > species_3

reaction_43

Ccp dephospholation

species_6 > species_4

reaction_44

Pcp dephospholation

species_9 > species_8

reaction_45

PCnp dephospholation

species_14 > species_12

reaction_46

PCn nonspecific degradation

species_12 > ∅

reaction_47

PCcp dephospholation

species_11 > species_10

reaction_48

Mr synthesized

∅ > species_16

reaction_49

Mr nonspecific degradation

species_16 > ∅

reaction_5

Mc translated into protein

∅ > species_4

reaction_50

Mr specific degradation

species_16 > ∅

reaction_51

Mr translated into protein

∅ > species_17

reaction_52

Rc transfered into nuclear

species_17 = species_18

reaction_53

Rc specific degradation

species_17 > ∅

reaction_54

Rc nonspecific degradation

species_17 > ∅

reaction_55

Rn specific degradation

species_18 > ∅

reaction_56

Rn nonspecific degradation

species_18 > ∅

reaction_6

Mc nonspecific degradation

species_5 > ∅

reaction_7

Cc phosphorylation

species_4 > species_6

reaction_8

Ccp specific degradation

species_6 > ∅

reaction_9

Mp synthesis

∅ > species_7

Parameters

Global parameters
reaction_0
reaction_1
reaction_10
reaction_11
reaction_12
reaction_13
reaction_14
reaction_15
reaction_16
reaction_17
reaction_18
reaction_19
reaction_2
reaction_20
reaction_21
reaction_22
reaction_23
reaction_24
reaction_25
reaction_26
reaction_27
reaction_28
reaction_29
reaction_3
reaction_30
reaction_31
reaction_32
reaction_33
reaction_34
reaction_35
reaction_36
reaction_37
reaction_38
reaction_39
reaction_4
reaction_40
reaction_41
reaction_42
reaction_43
reaction_44
reaction_45
reaction_46
reaction_47
reaction_48
reaction_49
reaction_5
reaction_50
reaction_51
reaction_52
reaction_53
reaction_54
reaction_55
reaction_56
reaction_6
reaction_7
reaction_8
reaction_9

Fixed species

Initial values

Functions and Rules

Events

Constraints

Note that constraints are not enforced in simulations. It remains the responsibility of the user to verify that simulation results satisfy these constraints.


Species:

Reactions:

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Toward a detailed computational model for the mammalian circadian clock.

  • Jean-Christophe Leloup
  • Albert Goldbeter
Proc. Natl. Acad. Sci. U.S.A. 2003; 100 (12): 7051-7056
Abstract
We present a computational model for the mammalian circadian clock based on the intertwined positive and negative regulatory loops involving the Per, Cry, Bmal1, Clock, and Rev-Erb alpha genes. In agreement with experimental observations, the model can give rise to sustained circadian oscillations in continuous darkness, characterized by an antiphase relationship between Per/Cry/Rev-Erbalpha and Bmal1 mRNAs. Sustained oscillations correspond to the rhythms autonomously generated by suprachiasmatic nuclei. For other parameter values, damped oscillations can also be obtained in the model. These oscillations, which transform into sustained oscillations when coupled to a periodic signal, correspond to rhythms produced by peripheral tissues. When incorporating the light-induced expression of the Per gene, the model accounts for entrainment of the oscillations by light-dark cycles. Simulations show that the phase of the oscillations can then vary by several hours with relatively minor changes in parameter values. Such a lability of the phase could account for physiological disorders related to circadian rhythms in humans, such as advanced or delayed sleep phase syndrome, whereas the lack of entrainment by light-dark cycles can be related to the non-24h sleep-wake syndrome. The model uncovers the possible existence of multiple sources of oscillatory behavior. Thus, in conditions where the indirect negative autoregulation of Per and Cry expression is inoperative, the model indicates the possibility that sustained oscillations might still arise from the negative autoregulation of Bmal1 expression.
The SBML for this model was obtained from the BioModels database (BioModels ID: BIOMD0000000074) This is model in continous darkness (DD) described in the article Toward a detailed computational model for the mammalian circadian clock This model features the full interlocked negative and positive regulation of Per,Cry,Bmal and REV-ERBalpha. The model exhibits robust oscillations quite independent of the initial conditions for teh parameters given. Each species is assigned zero as initial value, and the graph started at time=120h. Simulation results could be reproduced using Copasi 4.0.19(development) and roadRunner online. JWS Online curation: This model was curated by reproducing the figures as described in the BioModels Notes. No additional changes were made.