Location: Leloup, Goldbeter, 1998 @ 7e96457c1b1b / leloup_1998b_1.1model.cellml

Author:
Mona Zhu <devnull@localhost>
Date:
2011-02-02 17:15:49+13:00
Desc:
Adding 1.1 diagram
Permanent Source URI:
https://models.cellml.org/workspace/leloup_goldbeter_1998/rawfile/7e96457c1b1b46a2d960322820ef8a0f79e552ec/leloup_1998b_1.1model.cellml

<?xml version="1.0"?>
<model xmlns="http://www.cellml.org/cellml/1.1#" xmlns:cmeta="http://www.cellml.org/metadata/1.1#" cmeta:id="leloup_1998b_1.1model" name="leloup_1998b_1.1model">
	<!-- documentation -->
	<documentation xmlns="http://cellml.org/tmp-documentation">
		<article>
			<articleinfo>
				<title>A Model for Circadian Rhythms in Drosophila Incorporating the Formation of a Complex between the PER and TIM Proteins</title>
				<author>
					<firstname>Ethan</firstname>
					<surname>Choi</surname>
					<affiliation>
					<shortaffil>Auckland Bioengineering Institute, The University of Auckland</shortaffil>
					</affiliation>
				</author>
				<author>
					<firstname>Mona</firstname>
					<surname>Zhu</surname>
					<affiliation>
						<shortaffil>Auckland Bioengineering Institute, University of Auckland</shortaffil>
					</affiliation>
				</author>
			</articleinfo>
			<section id="sec_status">
				<title>Model Status</title>
				<para>This model has been built with the differential expressions in Leloup's 1998 paper for a circadian cycle in the case of a light-dark (12:12 LD) cycle. The model is a 1.1 modification of the orignal 1.0 model; it uses imports that are reusable in defining equations in the model. This file reproduces the diagrams in figure 4D-F (taking into account light-induced TIM degration via an oscillating v_dT). The initial conditions (for M_P, M_T, C_N, C, P_0, P_1, P_2, T_0, T_1, T_2) have been set after allowing the model to run till steady state to replicate figure4D-F. Note the rescaling of the publication diagrams for figure4E and F. This file is known to run in OpenCell only.</para>
			</section>
			<sect1 id="sec_structure">
				<title>Model Structure</title>
				<para>Abstract: The authors present a model for circadian oscillations of the Period (PER) and Timeless (TIM) proteins in Drosophila. The model for the circadian clock is based on multiple phosphorylation of PER and TIM and on the negative feedback exerted by a nuclear PER-TIM complex on the transcription of the perand tim genes. Periodic behavior occurs in a large domain of parameter space in the form of limit cycle oscillations. These sustained oscillations occur in conditions corresponding to continuous darkness or to entrainment by light-dark cycles and are in good agreement with experimental observations on the temporal variations of PER and TIM and of per and tim mRNAs. Birhythmicity (coexistence of two periodic regimes) and aperiodic oscillations (chaos) occur in a restricted range of parameter values. The results are compared to the predictions of a model based on the sole regulation by PER. Both the formation of a complex between PER and TIM and protein phosphorylation are found to favor oscillatory behavior. Determining how the period depends on several key parameters allows us to test possible molecular explanations proposed for the altered period in the perl and pers mutants. The extended model further allows the construction of phase-response curves based on the light-induced triggering of TIM degradation. These curves, established as a function of both the duration and magnitude of the effect of a light pulse, match the phase-response curves obtained experimentally in the wild type and pers mutant of Drosophila.</para>
				<para>A Model for Circadian Rhythms in Drosophila Incorporating the Formation of a Complex between the PER and TIM Proteins, Leloup JC, Goldbeter A, 1998, <emphasis>Journal of Biological Rhythms</emphasis>, 13, 70-87 <ulink url="http://www.ncbi.nlm.nih.gov/pubmed/9486845">PubMed ID: 9486845</ulink>
				</para>
				<informalfigure float="0" id="______">
					<mediaobject>
						<imageobject>
							<objectinfo>
								<title>Model Diagram</title>
							</objectinfo>
							<imagedata fileref="leloup_1998.png"/>
						</imageobject>
					</mediaobject>
					<caption>Scheme of the model for circadian oscillations in Drosophila involving negative regulation of gene expression by PER and TIM. per (MP) and tim (MT) mRNAs are synthesized in the nucleus and transferred into the cytosol, where they accumulate at the maximum rates vsP and vsT, respectively. There they are degraded enzymatically at the maximum rates, vmP and vmT, with the Michaelis constants, KmP and KmT. The rates of synthesis of the PER and TIM proteins, respectively proportional to MP and MT, are characterized by the apparent first-order rate constants ksP and ksT. Parameters ViP (ViT) and KiP (KiT) (i = 1, . . . 4) denote the maximum rate and Michaelis constant of the kinase(s) and phosphatase(s) involved in the reversible phosphorylation of P0 (T0) into P1 (T1) and P1 (T1) into P2 (T2), respectively. The fully phosphorylated forms (P2 and T2) are degraded by enzymes of maximum rate vdP and vdT and of Michaelis constants KdP and KdT and reversibly form a complex C (association and dissociation are characterized by the rate constants k3 and k4), which is transported into the nucleus at a rate characterized by the apparent first-order rate constant k1. Transport of the nuclear form of the PER-TIM complex (CN) into the cytosol is characterized by the apparent first-order rate constant k2. The negative feedback exerted by the nuclear PER-TIM complex on per and tim transcription is described by an equation of the Hill type (see first terms in Equations 1a and 1e) in which n denotes the degree of cooperativity and KIP and KIT are the threshold constants for repression.</caption>
				</informalfigure>
			</sect1>
		</article>
	</documentation>
	
	<!-- units -->
	<units name="hour">
		<unit multiplier="3600" units="second"/>
	</units>
	<units name="per_hour">
		<unit exponent="-1" units="hour"/>
	</units>
	<units name="per_litre">
		<unit exponent="-1" units="litre"/>
	</units>
	<units name="nanomolar">
		<unit prefix="nano" units="mole"/>
		<unit units="per_litre"/>
	</units>
	<units name="nanomolar_hour">
		<unit units="nanomolar"/>
		<unit units="per_hour"/>
	</units>
	<units name="per_nanomolar_hour">
		<unit exponent="-1" units="nanomolar"/>
		<unit units="per_hour"/>
	</units>
	
	<!-- components -->
	<component name="environment">
		<variable id="environment_time" name="time" public_interface="out" units="hour"/>
	</component>
	<component id="nucleus" name="nucleus">
		<variable name="time" private_interface="out" public_interface="in" units="hour"/>
		<variable initial_value="0.8" name="v_sP" private_interface="out" units="nanomolar_hour"/>
		<variable initial_value="0.8" name="v_mP" private_interface="out" units="nanomolar_hour"/>
		<variable initial_value="1" name="K_IP" private_interface="out" units="nanomolar"/>
		<variable initial_value="0.2" name="K_mP" private_interface="out" units="nanomolar"/>
		<variable initial_value="1" name="v_sT" private_interface="out" units="nanomolar_hour"/>
		<variable initial_value="0.7" name="v_mT" private_interface="out" units="nanomolar_hour"/>
		<variable initial_value="1" name="K_IT" private_interface="out" units="nanomolar"/>
		<variable initial_value="0.2" name="K_mT" private_interface="out" units="nanomolar"/>
		<variable name="k_d" private_interface="out" public_interface="in" units="per_hour"/>
		<variable initial_value="4" name="n" private_interface="out" units="dimensionless"/>
		<variable name="k_1" private_interface="out" public_interface="in" units="per_hour"/>
		<variable name="k_2" private_interface="out" public_interface="in" units="per_hour"/>
		<variable initial_value="0.01" name="k_dN" private_interface="out" units="per_hour"/>
		<variable name="C" private_interface="out" public_interface="in" units="nanomolar"/>
		<variable id="M_P" name="M_P" private_interface="in" public_interface="out" units="nanomolar"/>
		<variable id="M_T" name="M_T" private_interface="in" public_interface="out" units="nanomolar"/>
		<variable id="C_N" initial_value="1.203" name="C_N" private_interface="out" public_interface="out" units="nanomolar"/>
		<variable initial_value="0.09107" name="M_Pinit" private_interface="out" units="nanomolar"/>
		<variable initial_value="1.427" name="M_Tinit" private_interface="out" units="nanomolar"/>
		<math xmlns="http://www.w3.org/1998/Math/MathML">
			<apply>
				<eq/>
				<apply>
					<diff/>
					<bvar>
					<ci>time</ci>
					</bvar>
					<ci>C_N</ci>
				</apply>
				<apply>
					<minus/>
					<apply>
						<minus/>
						<apply>
							<times/>
							<ci>k_1</ci>
							<ci>C</ci>
						</apply>
						<apply>
							<times/>
							<ci>k_2</ci>
							<ci>C_N</ci>
						</apply>
					</apply>
					<apply>
						<times/>
						<ci>k_dN</ci>
						<ci>C_N</ci>
					</apply>
				</apply>
			</apply>
		</math>
	</component>
	<component id="cytosol" name="cytosol">
		<variable name="time" private_interface="out" public_interface="in" units="hour"/>
		<variable initial_value="1.2" name="k_1" public_interface="out" units="per_hour"/>
		<variable initial_value="0.2" name="k_2" public_interface="out" units="per_hour"/>
		<variable initial_value="1.2" name="k_3" private_interface="out" units="per_nanomolar_hour"/>
		<variable initial_value="0.6" name="k_4" private_interface="out" units="per_hour"/>
		<variable initial_value="0.01" name="k_d" private_interface="out" public_interface="out" units="per_hour"/>
		<variable initial_value="0.01" name="k_dC" units="per_hour"/>
		<variable name="P_0" private_interface="in" public_interface="out" units="nanomolar"/>
		<variable name="P_1" private_interface="in" public_interface="out" units="nanomolar"/>
		<variable name="P_2" private_interface="in" public_interface="out" units="nanomolar"/>
		<variable name="T_0" private_interface="in" public_interface="out" units="nanomolar"/>
		<variable name="T_1" private_interface="in" public_interface="out" units="nanomolar"/>
		<variable name="T_2" private_interface="in" public_interface="out" units="nanomolar"/>
		<variable name="M_P" private_interface="out" public_interface="in" units="nanomolar"/>
		<variable name="M_T" private_interface="out" public_interface="in" units="nanomolar"/>
		<variable name="C_N" public_interface="in" units="nanomolar"/>
		<variable id="C" initial_value="0.1790" name="C" private_interface="out" public_interface="out" units="nanomolar"/>
		<math xmlns="http://www.w3.org/1998/Math/MathML">
			<apply>
				<eq/>
				<apply>
					<diff/>
					<bvar>
						<ci>time</ci>
					</bvar>
					<ci>C</ci>
				</apply>
				<apply>
					<minus/>
					<apply>
						<plus/>
						<apply>
							<minus/>
							<apply>
								<minus/>
								<apply>
									<times/>
									<ci>k_3</ci>
									<ci>P_2</ci>
									<ci>T_2</ci>
								</apply>
								<apply>
									<times/>
									<ci>k_4</ci>
									<ci>C</ci>
								</apply>
							</apply>
							<apply>
								<times/>
								<ci>k_1</ci>
								<ci>C</ci>
							</apply>
						</apply>
						<apply>
							<times/>
							<ci>k_2</ci>
							<ci>C_N</ci>
						</apply>
					</apply>
					<apply>
						<times/>
						<ci>k_dC</ci>
						<ci>C</ci>
					</apply>
				</apply>
			</apply>
		</math>
	</component>
	<component id="PER" name="PER">
		<variable name="time" private_interface="out" public_interface="in" units="hour"/>
		<variable initial_value="8" name="V_1P" private_interface="out" units="nanomolar_hour"/>
		<variable initial_value="1" name="V_2P" private_interface="out" units="nanomolar_hour"/>
		<variable initial_value="8" name="V_3P" private_interface="out" units="nanomolar_hour"/>
		<variable initial_value="1" name="V_4P" private_interface="out" units="nanomolar_hour"/>
		<variable initial_value="2" name="K_1P" private_interface="out" units="nanomolar"/>
		<variable initial_value="2" name="K_2P" private_interface="out" units="nanomolar"/>
		<variable initial_value="2" name="K_3P" private_interface="out" units="nanomolar"/>
		<variable initial_value="2" name="K_4P" private_interface="out" units="nanomolar"/>
		<variable initial_value="0.2" name="K_dP" private_interface="out" units="nanomolar"/>
		<variable initial_value="2" name="v_dP" private_interface="out" units="nanomolar_hour"/>
		<variable initial_value="0.9" name="k_sP" private_interface="out" units="per_hour"/>
		<variable name="k_d" private_interface="out" public_interface="in" units="per_hour"/>
		<variable name="k_3" private_interface="out" public_interface="in" units="per_nanomolar_hour"/>
		<variable name="k_4" private_interface="out" public_interface="in" units="per_hour"/>
		<variable name="M_P" private_interface="out" public_interface="in" units="nanomolar"/>
		<variable name="T_2" private_interface="out" public_interface="in" units="nanomolar"/>
		<variable name="C" private_interface="out" public_interface="in" units="nanomolar"/>
		<variable id="P_0" name="P_0" private_interface="in" public_interface="out" units="nanomolar"/>
		<variable id="P_1" name="P_1" private_interface="in" public_interface="out" units="nanomolar"/>
		<variable id="P_2" name="P_2" private_interface="in" public_interface="out" units="nanomolar"/>
		<variable initial_value="0.02324" name="P_0init" private_interface="out" units="nanomolar"/>
		<variable initial_value="0.02210" name="P_1init" private_interface="out" units="nanomolar"/>
		<variable initial_value="0.01251" name="P_2init" private_interface="out" units="nanomolar"/>
	</component>
	<component id="TIM" name="TIM">
		<variable name="time" private_interface="out" public_interface="in" units="hour"/>
		<variable initial_value="8" name="V_1T" private_interface="out" units="nanomolar_hour"/>
		<variable initial_value="1" name="V_2T" private_interface="out" units="nanomolar_hour"/>
		<variable initial_value="8" name="V_3T" private_interface="out" units="nanomolar_hour"/>
		<variable initial_value="1" name="V_4T" private_interface="out" units="nanomolar_hour"/>
		<variable initial_value="2" name="K_1T" private_interface="out" units="nanomolar"/>
		<variable initial_value="2" name="K_2T" private_interface="out" units="nanomolar"/>
		<variable initial_value="2" name="K_3T" private_interface="out" units="nanomolar"/>
		<variable initial_value="2" name="K_4T" private_interface="out" units="nanomolar"/>
		<variable initial_value="0.2" name="K_dT" private_interface="out" units="nanomolar"/>
		<variable name="v_dT" private_interface="in" units="nanomolar_hour"/>
		<variable initial_value="0.9" name="k_sT" private_interface="out" units="per_hour"/>
		<variable name="k_d" private_interface="out" public_interface="in" units="per_hour"/>
		<variable name="k_3" private_interface="out" public_interface="in" units="per_nanomolar_hour"/>
		<variable name="k_4" private_interface="out" public_interface="in" units="per_hour"/>
		<variable name="M_T" private_interface="out" public_interface="in" units="nanomolar"/>
		<variable name="P_2" private_interface="out" public_interface="in" units="nanomolar"/>
		<variable name="C" private_interface="out" public_interface="in" units="nanomolar"/>
		<variable id="T_0" name="T_0" private_interface="in" public_interface="out" units="nanomolar"/>
		<variable id="T_1" name="T_1" private_interface="in" public_interface="out" units="nanomolar"/>
		<variable id="T_2" name="T_2" private_interface="in" public_interface="out" units="nanomolar"/>
		<variable initial_value="0.5420" name="T_0init" private_interface="out" units="nanomolar"/>
		<variable initial_value="0.8000" name="T_1init" private_interface="out" units="nanomolar"/>
		<variable initial_value="4.733" name="T_2init" private_interface="out" units="nanomolar"/>
	</component>
	<component id="PER_total" name="PER_total">
		<variable name="P_0" private_interface="out" public_interface="in" units="nanomolar"/>
		<variable name="P_1" private_interface="out" public_interface="in" units="nanomolar"/>
		<variable name="P_2" private_interface="out" public_interface="in" units="nanomolar"/>
		<variable name="C" private_interface="out" public_interface="in" units="nanomolar"/>
		<variable name="C_N" private_interface="out" public_interface="in" units="nanomolar"/>
		<variable id="P_t" name="P_t" private_interface="in" units="nanomolar"/>
	</component>
	<component id="TIM_total" name="TIM_total">
		<variable name="T_0" private_interface="out" public_interface="in" units="nanomolar"/>
		<variable name="T_1" private_interface="out" public_interface="in" units="nanomolar"/>
		<variable name="T_2" private_interface="out" public_interface="in" units="nanomolar"/>
		<variable name="C" private_interface="out" public_interface="in" units="nanomolar"/>
		<variable name="C_N" private_interface="out" public_interface="in" units="nanomolar"/>
		<variable id="T_t" name="T_t" private_interface="in" units="nanomolar"/>
	</component>
	<component cmeta:id="LD_cycle" name="LD_cycle">
		<variable name="time" public_interface="in" units="hour"/>
		<variable initial_value="3.141592653589793" name="PI" units="dimensionless"/>
		<variable initial_value="2" name="v_dT_dark" units="nanomolar_hour"/>
		<variable initial_value="4" name="v_dT_light" units="nanomolar_hour"/>
		<variable cmeta:id="v_dT" name="v_dT" public_interface="out" units="nanomolar_hour"/>
		<math xmlns="http://www.w3.org/1998/Math/MathML">
			<apply>
				<eq/>
				<ci>v_dT</ci>
				<piecewise>
					<piece>
						<ci>v_dT_dark</ci>
						<apply>
							<leq/>
							<apply>
								<sin/>
								<apply>
									<divide/>
									<apply>
										<times/>
										<ci>PI</ci>
										<ci>time</ci>
									</apply>
									<cn xmlns:cellml="http://www.cellml.org/cellml/1.1#" cellml:units="hour">12</cn>
								</apply>
							</apply>
							<cn xmlns:cellml="http://www.cellml.org/cellml/1.1#" cellml:units="dimensionless">0</cn>
						</apply>
					</piece>
					<otherwise>
						<ci>v_dT_light</ci>
					</otherwise>
				</piecewise>
			</apply>
		</math>
	</component>

	<!-- groups -->
	<group>
		<relationship_ref relationship="encapsulation"/>
			<component_ref component="cytosol">
				<component_ref component="PER">
					<component_ref component="P0"/>
					<component_ref component="P1"/>
					<component_ref component="P2"/>
				</component_ref>
				<component_ref component="TIM">
					<component_ref component="T0"/>
					<component_ref component="T1"/>
					<component_ref component="T2"/>
					<component_ref component="LD_cycle"/>
				</component_ref>
			</component_ref>
	</group>
	<group>
		<relationship_ref relationship="encapsulation"/>
			<component_ref component="nucleus">
				<component_ref component="MP"/>
				<component_ref component="MT"/>
			</component_ref>
	</group>
	<group>
		<relationship_ref relationship="encapsulation"/>
			<component_ref component="PER_total">
				<component_ref component="PERtotal"/>
			</component_ref>
	</group>
	<group>
		<relationship_ref relationship="encapsulation"/>
			<component_ref component="TIM_total">
				<component_ref component="TIMtotal"/>
			</component_ref>
	</group>
	
	<!-- imports -->
	<import xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="mRNAs.cellml">
		<component component_ref="interface" name="MP"/>
	</import>
	<import xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="mRNAs.cellml">
		<component component_ref="interface" name="MT"/>
	</import>
	<import xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="Stage0.cellml">
		<component component_ref="interface" name="P0"/>
	</import>
	<import xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="Stage0.cellml">
		<component component_ref="interface" name="T0"/>
	</import>
	<import xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="Stage1.cellml">
		<component component_ref="interface" name="P1"/>
	</import>
	<import xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="Stage1.cellml">
		<component component_ref="interface" name="T1"/>
	</import>
	<import xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="Stage2.cellml">
		<component component_ref="interface" name="P2"/>
	</import>
	<import xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="Stage2.cellml">
		<component component_ref="interface" name="T2"/>
	</import>
	<import xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="Totals.cellml">
		<component component_ref="interface" name="PERtotal"/>
	</import>
	<import xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="Totals.cellml">
		<component component_ref="interface" name="TIMtotal"/>
	</import>
	
	<!-- connections -->
	<connection>
		<map_components component_1="MP" component_2="nucleus"/>
		<map_variables variable_1="M" variable_2="M_P"/>
		<map_variables variable_1="time" variable_2="time"/>
		<map_variables variable_1="v_s" variable_2="v_sP"/>
		<map_variables variable_1="v_m" variable_2="v_mP"/>
		<map_variables variable_1="K_I" variable_2="K_IP"/>
		<map_variables variable_1="K_m" variable_2="K_mP"/>
		<map_variables variable_1="C_N" variable_2="C_N"/>
		<map_variables variable_1="n" variable_2="n"/>
		<map_variables variable_1="k_d" variable_2="k_d"/>
		<map_variables variable_1="M_init" variable_2="M_Pinit"/>
	</connection>
	
	<connection>
		<map_components component_1="MT" component_2="nucleus"/>
		<map_variables variable_1="M" variable_2="M_T"/>
		<map_variables variable_1="time" variable_2="time"/>
		<map_variables variable_1="v_s" variable_2="v_sT"/>
		<map_variables variable_1="v_m" variable_2="v_mT"/>
		<map_variables variable_1="K_I" variable_2="K_IT"/>
		<map_variables variable_1="K_m" variable_2="K_mT"/>
		<map_variables variable_1="C_N" variable_2="C_N"/>
		<map_variables variable_1="n" variable_2="n"/>
		<map_variables variable_1="k_d" variable_2="k_d"/>
		<map_variables variable_1="M_init" variable_2="M_Tinit"/>
	</connection>
	<connection>
		<map_components component_1="cytosol" component_2="PER"/>
		<map_variables variable_1="time" variable_2="time"/>
		<map_variables variable_1="k_3" variable_2="k_3"/>
		<map_variables variable_1="k_4" variable_2="k_4"/>
		<map_variables variable_1="k_d" variable_2="k_d"/>
		<map_variables variable_1="M_P" variable_2="M_P"/>
		<map_variables variable_1="C" variable_2="C"/>
		<map_variables variable_1="P_0" variable_2="P_0"/>
		<map_variables variable_1="P_1" variable_2="P_1"/>
		<map_variables variable_1="P_2" variable_2="P_2"/>
	</connection><connection>
		<map_components component_1="cytosol" component_2="TIM"/>
		<map_variables variable_1="time" variable_2="time"/>
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