- Author:
- pmr2.import <nobody@models.cellml.org>
- Date:
- 2007-07-09 01:11:43+12:00
- Desc:
- committing version01 of haugh_2004
- Permanent Source URI:
- https://models.cellml.org/workspace/haugh_2004/rawfile/41e51eb95323d4bd7a9834ba2a1a835a6ec22baf/haugh_2004.cellml
<?xml version='1.0' encoding='utf-8'?>
<!-- FILE : haugh_model_2004.xml
CREATED : 9th July 2007
LAST MODIFIED : 9th July 2007
AUTHOR : Catherine Lloyd
Bioengineering Institute
The University of Auckland
MODEL STATUS : This model conforms to the CellML 1.1 Specification.
DESCRIPTION : This file contains a CellML description of Jason Haugh's 2004 mathematical model of human growth hormone-stimulated cell proliferation.
CHANGES:
--><model xmlns="http://www.cellml.org/cellml/1.0#" xmlns:cmeta="http://www.cellml.org/metadata/1.0#" xmlns:dc="http://purl.org/dc/elements/1.1/" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" xmlns:bqs="http://www.cellml.org/bqs/1.0#" xmlns:cellml="http://www.cellml.org/cellml/1.0#" xmlns:dcterms="http://purl.org/dc/terms/" xmlns:vCard="http://www.w3.org/2001/vcard-rdf/3.0#" cmeta:id="haugh_model_2004" name="haugh_model_2004_version01">
<documentation xmlns="http://cellml.org/tmp-documentation">
<article>
<articleinfo>
<title>Mathematical model of human growth hormone (hGH)-stimulated cell proliferation explains the efficacy of hGH variants as receptor agonists or antagonists</title>
<author>
<firstname>Catherine</firstname>
<surname>Lloyd</surname>
<affiliation>
<shortaffil>Bioengineering Institute, University of Auckland</shortaffil>
</affiliation>
</author>
</articleinfo>
<sect1 id="sec_structure">
<title>Model Structure</title>
<para>
Human growth hormone (hGH) is secreted by the pituitary gland and it has several functions, the most important of which is the control of skeletal growth. To mediate its effects, hGH must first bind to its specific cell surface receptor, and it can do so through 2 different binding sites. Hormone-receptor binding is ordered and sequential with hGH initially binding to the receptor via site 1 to form a 1:1 receptor complex. A second receptor is then recruited and bound via site 2 on the hGH ligand to form a 1:2 complex. This receptor dimerisation process is required for intracellular signalling and the stimulation of cell proliferation to occur.
</para>
<para>
A high resolution crystal structure of the ligand-receptor complex has been published, and several mathematical models describing the interactions between hGH and its receptor have also been published. Yet despite all this information, the mechanisms underlying many experimental observations remain poorly understood. The CellML model described here is based on Jason Haugh's published model of hGH-receptor binding kinetics. This mathematical model builds on those already published by including a description of the kinetics of receptor internalisation, and thus allows the cell to have a mechanism of controlling the rate of cell proliferation. In this study the kinetics of hGH-receptor binding, dimerisation, and trafficking have been combined to create a mathematical model capable of accounting for experimental results.
</para>
<informalfigure float="0" id="fig_reaction_diagram">
<mediaobject>
<imageobject>
<objectinfo>
<title>model diagram</title>
</objectinfo>
<imagedata fileref="haugh_2004.png"/>
</imageobject>
</mediaobject>
<caption>A schematic diagram of the kinetic model of human growth hormone (hGH) receptor binding and trafficking. The extracellular ligand (L), hGH, has two sites for binding the hGH receptor (R), and these are shown in cerise and cyan in the diagram and are numbered 1 and 2 respectively. Site 1 always binds to the receptor first to form a 1:1 ligand-receptor complex (C). A 1:2 dimer (D) may then form through the binding of a second receptor to site 2 of the ligand. Dimer dissociation can occur the uncoupling of either hGH site 1 or site 2, but the 1:1 ligand-receptor complexes bound through site 2 dissociate much faster than those bound through site 1. Dimerised complexes (D) are internalised at a higher rate than are free receptors (R) or 1:1 complexes (C), and while internalised dimers are always degraded, internalised 1:1 complexes or free receptors can either be degraded or recycled to the cell surface. A steady state is maintained through de novo receptor synthesis.</caption>
</informalfigure>
<para>
The complete original paper reference is cited below:
</para>
<para>
<ulink url="http://pubs.acs.org/cgi-bin/abstract.cgi/bipret/2004/20/i05/abs/bp0499101.html">Mathematical model of human growth hormone (hGH)-stimulated cell proliferation explains the efficacy of hGH variants as receptor agonists or antagonists</ulink>, Jason M. Haugh, 2004, <ulink url="http://pubs.acs.org/journals/bipret/index.html">
<emphasis>Biotechnology Progress</emphasis>
</ulink>, volume 4, issue 5, 948-955. (<ulink url="http://pubs.acs.org/cgi-bin/article.cgi/bipret/2004/20/i05/html/bp0499101.html">Full text (HTML)</ulink> and <ulink url="http://pubs.acs.org/cgi-bin/article.cgi/bipret/2004/20/i05/pdf/bp0499101.pdf">PDF</ulink> versions of the article are available to journal subscribers on the <emphasis>Biotechnology Progress</emphasis> website.) <ulink url="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=15458315&query_hl=1&itool=pubmed_docsum">PubMed ID: 15458315</ulink>
</para>
</sect1>
</article>
</documentation>
<units name="nanomolar">
<unit units="mole" prefix="nano"/>
<unit units="litre" exponent="-1"/>
</units>
<units name="minute">
<unit units="second" multiplier="60.0"/>
</units>
<units name="flux">
<unit units="nanomolar"/>
<unit units="minute" exponent="-1"/>
</units>
<units name="first_order_rate_constant">
<unit units="minute" exponent="-1"/>
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</rdf:Description>
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<variable units="second_order_rate_constant" public_interface="in" name="kf1"/>
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<math xmlns="http://www.w3.org/1998/Math/MathML">
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<rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
<rdf:Description rdf:about="D">
<dc:title>D</dc:title>
<dcterms:alternative>1:2 hGH-receptor dimer complex</dcterms:alternative>
</rdf:Description>
</rdf:RDF>
<variable units="nanomolar" public_interface="out" name="D" initial_value="0.0"/>
<variable units="first_order_rate_constant" public_interface="in" name="k_x1"/>
<variable units="second_order_rate_constant" public_interface="in" name="kx2"/>
<variable units="first_order_rate_constant" public_interface="in" name="k_x2"/>
<variable units="first_order_rate_constant" public_interface="in" name="ke"/>
<variable units="nanomolar" public_interface="in" name="C"/>
<variable units="nanomolar" public_interface="in" name="R"/>
<variable units="minute" public_interface="in" name="time"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
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<apply>
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<ci> ke </ci>
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<component cmeta:id="R" name="R">
<rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
<rdf:Description rdf:about="R">
<dc:title>R</dc:title>
<dcterms:alternative>free hGH-receptor</dcterms:alternative>
</rdf:Description>
</rdf:RDF>
<variable units="nanomolar" public_interface="out" name="R" initial_value="0.0"/>
<variable units="second_order_rate_constant" public_interface="in" name="kf1"/>
<variable units="first_order_rate_constant" public_interface="in" name="kr1"/>
<variable units="second_order_rate_constant" public_interface="in" name="kx2"/>
<variable units="first_order_rate_constant" public_interface="in" name="k_x2"/>
<variable units="first_order_rate_constant" public_interface="in" name="kt"/>
<variable units="first_order_rate_constant" public_interface="in" name="k_x1"/>
<variable units="first_order_rate_constant" public_interface="in" name="krec"/>
<variable units="nanomolar" public_interface="in" name="D"/>
<variable units="nanomolar" public_interface="in" name="Ri"/>
<variable units="nanomolar" public_interface="in" name="L"/>
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<variable units="flux" public_interface="in" name="Vs"/>
<variable units="minute" public_interface="in" name="time"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
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<ci> R </ci>
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<ci> Vs </ci>
<apply>
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<ci> kr1 </ci>
<ci> C </ci>
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<apply>
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<apply>
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<ci> k_x2 </ci>
<apply>
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<cn cellml:units="dimensionless"> 2.0 </cn>
<ci> k_x1 </ci>
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<ci> D </ci>
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<apply>
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<ci> Ri </ci>
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<apply>
<times/>
<apply>
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<apply>
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<apply>
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<ci> C </ci>
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<ci> kt </ci>
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<ci> R </ci>
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<rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
<rdf:Description rdf:about="Ri">
<dc:title>Ri</dc:title>
<dcterms:alternative>internalised hGH-receptor</dcterms:alternative>
</rdf:Description>
</rdf:RDF>
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<variable units="first_order_rate_constant" public_interface="in" name="krec"/>
<variable units="first_order_rate_constant" public_interface="in" name="kdeg"/>
<variable units="first_order_rate_constant" public_interface="in" name="kt"/>
<variable units="nanomolar" public_interface="in" name="R"/>
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<variable units="minute" public_interface="in" name="time"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
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<ci> Ri </ci>
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<apply>
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<ci> kt </ci>
<apply>
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<ci> R </ci>
<ci> C </ci>
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<apply>
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<apply>
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<ci> krec </ci>
<ci> kdeg </ci>
</apply>
<ci> Ri </ci>
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</component>
<component cmeta:id="R0" name="R0">
<rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
<rdf:Description rdf:about="R0">
<dc:title>R0</dc:title>
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</rdf:Description>
</rdf:RDF>
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<math xmlns="http://www.w3.org/1998/Math/MathML">
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<ci> R </ci>
<apply>
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<cn cellml:units="dimensionless"> 2.0 </cn>
<apply>
<divide/>
<ci> ke </ci>
<ci> kt </ci>
</apply>
<apply>
<plus/>
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<apply>
<divide/>
<ci> krec </ci>
<ci> kdeg </ci>
</apply>
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</apply>
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</component>
<component name="signal">
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<variable units="dimensionless" public_interface="in" name="kappaE"/>
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<math xmlns="http://www.w3.org/1998/Math/MathML">
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<ci> R0 </ci>
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</component>
<component name="model_parameters">
<variable units="second_order_rate_constant" public_interface="out" name="kf1" initial_value="0.1"/>
<variable units="first_order_rate_constant" public_interface="out" name="kr1"/>
<variable units="second_order_rate_constant" public_interface="out" name="kx2" initial_value="4.83"/>
<variable units="first_order_rate_constant" public_interface="out" name="k_x2" initial_value="0.016"/>
<variable units="first_order_rate_constant" public_interface="out" name="k_x1"/>
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<variable units="first_order_rate_constant" public_interface="out" name="kt" initial_value="0.005"/>
<!-- Note: the model author was contacted and values for the following 3 parameters were requested. -->
<variable units="first_order_rate_constant" public_interface="out" name="krec" initial_value="0.0"/>
<variable units="first_order_rate_constant" public_interface="out" name="kdeg" initial_value="0.05"/>
<variable units="flux" public_interface="out" name="Vs" initial_value="10.0"/>
<variable units="nanomolar" public_interface="out" name="L" initial_value="0.01"/>
<variable units="dimensionless" public_interface="out" name="kappaE" initial_value="0.20"/>
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<apply>
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<connection>
<map_components component_2="environment" component_1="D"/>
<map_variables variable_2="time" variable_1="time"/>
</connection>
<connection>
<map_components component_2="environment" component_1="R"/>
<map_variables variable_2="time" variable_1="time"/>
</connection>
<connection>
<map_components component_2="environment" component_1="Ri"/>
<map_variables variable_2="time" variable_1="time"/>
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<map_variables variable_2="D" variable_1="D"/>
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<map_variables variable_2="R" variable_1="R"/>
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<map_variables variable_2="R" variable_1="R"/>
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<connection>
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</connection>
<connection>
<map_components component_2="signal" component_1="D"/>
<map_variables variable_2="D" variable_1="D"/>
</connection>
<connection>
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<connection>
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<map_variables variable_2="kf1" variable_1="kf1"/>
<map_variables variable_2="kr1" variable_1="kr1"/>
<map_variables variable_2="kx2" variable_1="kx2"/>
<map_variables variable_2="k_x2" variable_1="k_x2"/>
<map_variables variable_2="kt" variable_1="kt"/>
<map_variables variable_2="L" variable_1="L"/>
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<connection>
<map_components component_2="model_parameters" component_1="D"/>
<map_variables variable_2="k_x1" variable_1="k_x1"/>
<map_variables variable_2="kx2" variable_1="kx2"/>
<map_variables variable_2="k_x2" variable_1="k_x2"/>
<map_variables variable_2="ke" variable_1="ke"/>
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<connection>
<map_components component_2="model_parameters" component_1="R"/>
<map_variables variable_2="kf1" variable_1="kf1"/>
<map_variables variable_2="kr1" variable_1="kr1"/>
<map_variables variable_2="kx2" variable_1="kx2"/>
<map_variables variable_2="k_x2" variable_1="k_x2"/>
<map_variables variable_2="kt" variable_1="kt"/>
<map_variables variable_2="k_x1" variable_1="k_x1"/>
<map_variables variable_2="krec" variable_1="krec"/>
<map_variables variable_2="Vs" variable_1="Vs"/>
<map_variables variable_2="L" variable_1="L"/>
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<connection>
<map_components component_2="model_parameters" component_1="Ri"/>
<map_variables variable_2="krec" variable_1="krec"/>
<map_variables variable_2="kdeg" variable_1="kdeg"/>
<map_variables variable_2="kt" variable_1="kt"/>
</connection>
<connection>
<map_components component_2="model_parameters" component_1="R0"/>
<map_variables variable_2="ke" variable_1="ke"/>
<map_variables variable_2="kt" variable_1="kt"/>
<map_variables variable_2="krec" variable_1="krec"/>
<map_variables variable_2="kdeg" variable_1="kdeg"/>
</connection>
<connection>
<map_components component_2="model_parameters" component_1="signal"/>
<map_variables variable_2="kappaE" variable_1="kappaE"/>
</connection>
<rdf:RDF>
<rdf:Bag rdf:about="rdf:#fa7bf1fe-e354-4761-9c32-6e997c5b56d3">
<rdf:li>growth hormone</rdf:li>
<rdf:li>endocrine</rdf:li>
<rdf:li>pituitary</rdf:li>
</rdf:Bag>
<rdf:Seq rdf:about="rdf:#d03ef4a9-d16a-4981-a2e6-1bc402ace599">
<rdf:li rdf:resource="rdf:#0e4000ae-bce1-4f7e-aca1-f736f385eb2b"/>
</rdf:Seq>
<rdf:Description rdf:about="rdf:#e81a6abe-79fb-457d-8b93-a4af106e6d31">
<dcterms:W3CDTF>2007-07-09T00:00:00+00:00</dcterms:W3CDTF>
</rdf:Description>
<rdf:Description rdf:about="">
<dc:publisher>The University of Auckland, Bioengineering Institute</dc:publisher>
<cmeta:comment rdf:resource="rdf:#acb0c628-9910-4856-ac47-9e10c8cd2c76"/>
<dcterms:created rdf:resource="rdf:#e81a6abe-79fb-457d-8b93-a4af106e6d31"/>
<dc:creator rdf:resource="rdf:#6ba92720-49b4-4c43-b061-915b2b95b6f5"/>
<cmeta:modification rdf:resource="rdf:#2cae4b26-cc50-42b0-b21b-2c5c2ebbcd1e"/>
</rdf:Description>
<rdf:Description rdf:about="rdf:#89e1701b-ace7-4c4a-b002-4e9f7ba189ad">
<dcterms:W3CDTF>2007-09-02T16:59:12+12:00</dcterms:W3CDTF>
</rdf:Description>
<rdf:Description rdf:about="rdf:#600642bc-3efd-4737-9d5f-589551c26a28">
<bqs:Pubmed_id>15458315</bqs:Pubmed_id>
<bqs:JournalArticle rdf:resource="rdf:#d61b6f13-9f0a-4f65-8a1e-e97c075ed080"/>
</rdf:Description>
<rdf:Description rdf:about="rdf:#bbe4120e-ff72-4785-b668-477adf870615">
<vCard:Given>Catherine</vCard:Given>
<vCard:Family>Lloyd</vCard:Family>
<vCard:Other>May</vCard:Other>
</rdf:Description>
<rdf:Description rdf:about="#haugh_model_2004">
<dc:title>
Jason Haugh's 2004 mathematical model of human growth hormone-stimulated cell proliferation.
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