- Author:
- pmr2.import <nobody@models.cellml.org>
- Date:
- 2007-07-03 03:01:38+12:00
- Desc:
- committing version01 of dempsher_gann_phair_1984
- Permanent Source URI:
- https://models.cellml.org/workspace/dempsher_gann_phair_1984/rawfile/ad7d20dbfb8930d4499abd7d2a0c565809f6520c/dempsher_gann_phair_1984.cellml
<?xml version='1.0' encoding='utf-8'?>
<!-- FILE : dempsher_model_1984.xml
CREATED : 28th June 2007
LAST MODIFIED : 28th June 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 Dempsher et al.'s 1984 mathematical model of ACTH-stimulated cortisol secretion.
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="dempsher_model_1984" name="dempsher_gann_phair_model_1984_version01">
<documentation xmlns="http://cellml.org/tmp-documentation">
<article>
<articleinfo>
<title>A mechanistic model of ACTH-stimulated cortisol secretion</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>
Advances in the study of cortisol biosynthesis indicate that adrenocorticotropin (ACTH) stimulates steroid secretion by facilitating the delivery of free cholesterol to the side chain cleavage (scc) enzyme. ACTH binds to one or more specific receptors in the adrenocortical cell membrane (represented by A and B in the figure below) which has the effect of activating adenylate cyclase (ACase). The cytosolic concentration of adenosine 3,5-cyclic monophosphate (cAMP) increases, in turn a) activating cholesterol ester (CE) hydrolase, which catalyses the conversion of cholesterol ester into free cholesterol, and b) facilitating the transfer of cholesterol within the mitochondrion to a site accessible to the scc enzyme. Furthermore, low density lipoprotein receptor-mediated uptake of plasma cholesterol together with cytosolic cholesterol synthesis provide substrate for steroid synthesis, and both these processes can be controlled by an intracellular pool of cholesterol.
</para>
<para>
In their 1984 publication, Dempsher <emphasis>et al.</emphasis> describe all these physiological phenomena in a mathematical model of ACTH-stimulated cortisol secretion (the complete original paper reference is cited below). Steps in the biosynthetic pathway are described using first-order linear differential equations, and the results of the model simulations were compared, and were consistent with, experimental data.
The corticotropin-releasing hormone (CRH) is synthesised in the hypothalamus and is carried to the anterior pituitary gland where it stimulates cells to produce adrenocorticotrophic hormone (ACTH). In turn, ACTH stimulates the synthesis and secretion of cortisol (F). Cortisol exerts a negative feedback effect on the ACTH secretion in the pituitary and also suppresses CRH synthesis in the hypothalamus. In addition, there is also a negative feedback effect of ACTH on the secretion of CRH. Therefore the entire process can be thought of as a self-regulating system, as summarised in <xref linkend="fig_reaction_diagram"/> below).
</para>
<para>
<ulink url="http://ajpregu.physiology.org/cgi/content/abstract/246/4/R587">A mechanistic model of ACTH-stimulated cortisol secretion</ulink>, D.P. Dempsher, D.S. Gann, and R.D. Phair, 1984, <ulink url="http://ajpregu.physiology.org/">
<emphasis>American Journal of Physiology</emphasis>
</ulink>, 246, R587-R596. (A <ulink url="http://ajpregu.physiology.org/cgi/reprint/246/4/R587">PDF</ulink> version of the article is available to journal subscribers on the <emphasis>American Journal of Physiology</emphasis> website.) <ulink url="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=6326602&query_hl=1&itool=pubmed_docsum">PubMed ID: 6326602</ulink>
</para>
<informalfigure float="0" id="fig_reaction_diagram">
<mediaobject>
<imageobject>
<objectinfo>
<title>model diagram</title>
</objectinfo>
<imagedata fileref="dempsher_model_1984.gif"/>
</imageobject>
</mediaobject>
<caption>Schematic diagram of the model describing the effects of ACTH on cortisol secretion. (note that ECF represents the extracellular fluid).</caption>
</informalfigure>
</sect1>
</article>
</documentation>
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<ci> HY </ci>
<ci> HYPR </ci>
</apply>
<apply>
<times/>
<ci> LH </ci>
<ci> CORT </ci>
</apply>
</apply>
</apply>
</math>
</component>
<component name="model_parameters">
<variable units="first_order_rate_constant" public_interface="out" name="Lmtr" initial_value="1.65"/>
<variable units="first_order_rate_constant" public_interface="out" name="Kbac" initial_value="10.0"/>
<variable units="first_order_rate_constant" public_interface="out" name="Kcb" initial_value="0.01"/>
<variable units="first_order_rate_constant" public_interface="out" name="Kcf" initial_value="0.00033"/>
<variable units="flux" public_interface="out" name="Vm" initial_value="1890.0"/>
<variable units="nM_g" public_interface="out" name="Km" initial_value="270.0"/>
<variable units="flux" public_interface="out" name="Vmptr" initial_value="500.0"/>
<variable units="nM_g" public_interface="out" name="Kmptr" initial_value="150.0"/>
<variable units="first_order_rate_constant" public_interface="out" name="AH" initial_value="16.4"/>
<variable units="first_order_rate_constant" public_interface="out" name="HY" initial_value="16.4"/>
</component>
<connection>
<map_components component_2="environment" component_1="cAMP"/>
<map_variables variable_2="time" variable_1="time"/>
</connection>
<connection>
<map_components component_2="environment" component_1="IS"/>
<map_variables variable_2="time" variable_1="time"/>
</connection>
<connection>
<map_components component_2="environment" component_1="V"/>
<map_variables variable_2="time" variable_1="time"/>
</connection>
<connection>
<map_components component_2="environment" component_1="W"/>
<map_variables variable_2="time" variable_1="time"/>
</connection>
<connection>
<map_components component_2="environment" component_1="CHOC"/>
<map_variables variable_2="time" variable_1="time"/>
</connection>
<connection>
<map_components component_2="environment" component_1="CHOM"/>
<map_variables variable_2="time" variable_1="time"/>
</connection>
<connection>
<map_components component_2="environment" component_1="CHOL"/>
<map_variables variable_2="time" variable_1="time"/>
</connection>
<connection>
<map_components component_2="environment" component_1="Kmtr"/>
<map_variables variable_2="time" variable_1="time"/>
</connection>
<connection>
<map_components component_2="environment" component_1="Kfor"/>
<map_variables variable_2="time" variable_1="time"/>
</connection>
<connection>
<map_components component_2="environment" component_1="CHON"/>
<map_variables variable_2="time" variable_1="time"/>
</connection>
<connection>
<map_components component_2="environment" component_1="PREG"/>
<map_variables variable_2="time" variable_1="time"/>
</connection>
<connection>
<map_components component_2="environment" component_1="PRO"/>
<map_variables variable_2="time" variable_1="time"/>
</connection>
<connection>
<map_components component_2="environment" component_1="HYPR"/>
<map_variables variable_2="time" variable_1="time"/>
</connection>
<connection>
<map_components component_2="environment" component_1="CORT"/>
<map_variables variable_2="time" variable_1="time"/>
</connection>
<connection>
<map_components component_2="IS" component_1="cAMP"/>
<map_variables variable_2="cAMP" variable_1="cAMP"/>
</connection>
<connection>
<map_components component_2="V" component_1="IS"/>
<map_variables variable_2="IS" variable_1="IS"/>
</connection>
<connection>
<map_components component_2="CHOC" component_1="W"/>
<map_variables variable_2="CHOC" variable_1="CHOC"/>
<map_variables variable_2="W" variable_1="W"/>
</connection>
<connection>
<map_components component_2="CHOM" component_1="CHOC"/>
<map_variables variable_2="CHOM" variable_1="CHOM"/>
<map_variables variable_2="CHOC" variable_1="CHOC"/>
</connection>
<connection>
<map_components component_2="CHOC" component_1="Kmtr"/>
<map_variables variable_2="Kmtr" variable_1="Kmtr"/>
</connection>
<connection>
<map_components component_2="V" component_1="CHOC"/>
<map_variables variable_2="V" variable_1="V"/>
</connection>
<connection>
<map_components component_2="model_parameters" component_1="CHOC"/>
<map_variables variable_2="Lmtr" variable_1="Lmtr"/>
</connection>
<connection>
<map_components component_2="CHOM" component_1="CHON"/>
<map_variables variable_2="CHOM" variable_1="CHOM"/>
<map_variables variable_2="CHON" variable_1="CHON"/>
</connection>
<connection>
<map_components component_2="CHOM" component_1="CHOL"/>
<map_variables variable_2="CHOM" variable_1="CHOM"/>
<map_variables variable_2="CHOL" variable_1="CHOL"/>
</connection>
<connection>
<map_components component_2="Kfor" component_1="CHOM"/>
<map_variables variable_2="Kfor" variable_1="Kfor"/>
</connection>
<connection>
<map_components component_2="CHOM" component_1="Kmtr"/>
<map_variables variable_2="Kmtr" variable_1="Kmtr"/>
</connection>
<connection>
<map_components component_2="model_parameters" component_1="CHOM"/>
<map_variables variable_2="Lmtr" variable_1="Lmtr"/>
<map_variables variable_2="Kbac" variable_1="Kbac"/>
<map_variables variable_2="Kcb" variable_1="Kcb"/>
<map_variables variable_2="Kcf" variable_1="Kcf"/>
</connection>
<connection>
<map_components component_2="model_parameters" component_1="CHOL"/>
<map_variables variable_2="Kcb" variable_1="Kcb"/>
<map_variables variable_2="Kcf" variable_1="Kcf"/>
</connection>
<connection>
<map_components component_2="Kmtr" component_1="IS"/>
<map_variables variable_2="IS" variable_1="IS"/>
</connection>
<connection>
<map_components component_2="Kfor" component_1="IS"/>
<map_variables variable_2="IS" variable_1="IS"/>
</connection>
<connection>
<map_components component_2="Kfor" component_1="CHON"/>
<map_variables variable_2="Kfor" variable_1="Kfor"/>
</connection>
<connection>
<map_components component_2="model_parameters" component_1="CHON"/>
<map_variables variable_2="Vm" variable_1="Vm"/>
<map_variables variable_2="Kbac" variable_1="Kbac"/>
<map_variables variable_2="Km" variable_1="Km"/>
</connection>
<connection>
<map_components component_2="PREG" component_1="CHON"/>
<map_variables variable_2="CHON" variable_1="CHON"/>
</connection>
<connection>
<map_components component_2="model_parameters" component_1="PREG"/>
<map_variables variable_2="Vmptr" variable_1="Vmptr"/>
<map_variables variable_2="Kmptr" variable_1="Kmptr"/>
<map_variables variable_2="Vm" variable_1="Vm"/>
<map_variables variable_2="Km" variable_1="Km"/>
</connection>
<connection>
<map_components component_2="PREG" component_1="PRO"/>
<map_variables variable_2="PREG" variable_1="PREG"/>
</connection>
<connection>
<map_components component_2="model_parameters" component_1="PRO"/>
<map_variables variable_2="Vmptr" variable_1="Vmptr"/>
<map_variables variable_2="Kmptr" variable_1="Kmptr"/>
<map_variables variable_2="AH" variable_1="AH"/>
</connection>
<connection>
<map_components component_2="PRO" component_1="HYPR"/>
<map_variables variable_2="PRO" variable_1="PRO"/>
</connection>
<connection>
<map_components component_2="model_parameters" component_1="HYPR"/>
<map_variables variable_2="HY" variable_1="HY"/>
<map_variables variable_2="AH" variable_1="AH"/>
</connection>
<connection>
<map_components component_2="HYPR" component_1="CORT"/>
<map_variables variable_2="HYPR" variable_1="HYPR"/>
</connection>
<connection>
<map_components component_2="model_parameters" component_1="CORT"/>
<map_variables variable_2="HY" variable_1="HY"/>
</connection>
<rdf:RDF>
<rdf:Bag rdf:about="rdf:#d0703452-f4e5-4e86-936d-9c95368b07a3">
<rdf:li>cortisol</rdf:li>
<rdf:li>HPA axis</rdf:li>
</rdf:Bag>
<rdf:Seq rdf:about="rdf:#1e1edc53-8ecc-4d3e-9599-b840c42f1d10">
<rdf:li rdf:resource="rdf:#74cfeed3-fe5a-4c6d-9146-1f7571651e16"/>
<rdf:li rdf:resource="rdf:#49fe8325-99eb-407c-897b-ecc6b816c3aa"/>
<rdf:li rdf:resource="rdf:#753489a5-3e71-4c1a-81d9-7010f77e05e2"/>
</rdf:Seq>
<rdf:Description rdf:about="">
<dc:publisher>The University of Auckland, Bioengineering Institute</dc:publisher>
<cmeta:comment rdf:resource="rdf:#0658c637-7576-42f3-b56a-4de2f45a0b3a"/>
<dcterms:created rdf:resource="rdf:#22201077-f2e2-4cac-b4d8-4826c632b54d"/>
<dc:creator rdf:resource="rdf:#d3b10bee-3260-4bfb-91b9-55d84a2efa68"/>
</rdf:Description>
<rdf:Description rdf:about="/Kfor">
<dcterms:alternative>rate for the flux of cholesterol onto the side chain cleavage enzyme</dcterms:alternative>
<dc:title>Kfor</dc:title>
</rdf:Description>
<rdf:Description rdf:about="rdf:#0657bf45-30da-4275-9e3a-471729aee554">
<dc:subject rdf:resource="rdf:#b439fc89-5054-4ad1-b610-913c00953110"/>
</rdf:Description>
<rdf:Description rdf:about="rdf:#4abb09a2-275f-4066-8361-92a3e6f30e88">
<vCard:Given>R</vCard:Given>
<vCard:Family>Phair</vCard:Family>
<vCard:Other>D</vCard:Other>
</rdf:Description>
<rdf:Description rdf:about="/IS">
<dcterms:alternative>intracellular signal</dcterms:alternative>
<dc:title>IS</dc:title>
</rdf:Description>
<rdf:Description rdf:about="rdf:#48a8d31a-49ac-4c39-baf8-aae1b70fbb9f">
<vCard:Orgname>The University of Auckland</vCard:Orgname>
<vCard:Orgunit>The Bioengineering Institute</vCard:Orgunit>
</rdf:Description>
<rdf:Description rdf:about="/V">
<dcterms:alternative>cholesterol flux to a pool of free cholesterol</dcterms:alternative>
<dc:title>V</dc:title>
</rdf:Description>
<rdf:Description rdf:about="/W">
<dcterms:alternative>flux of free cholesterol from de novo synthesis</dcterms:alternative>
<dc:title>W</dc:title>
</rdf:Description>
<rdf:Description rdf:about="rdf:#b439fc89-5054-4ad1-b610-913c00953110">
<bqs:subject_type>keyword</bqs:subject_type>
<rdf:value rdf:resource="rdf:#d0703452-f4e5-4e86-936d-9c95368b07a3"/>
</rdf:Description>
<rdf:Description rdf:about="rdf:#df794626-99b8-4fef-b993-418acfbe498e">
<bqs:Pubmed_id>6326602</bqs:Pubmed_id>
<bqs:JournalArticle rdf:resource="rdf:#1aa7d171-2410-417a-932d-937315262ab6"/>
</rdf:Description>
<rdf:Description rdf:about="/PREG">
<dcterms:alternative>mitochondrial pregnolone</dcterms:alternative>
<dc:title>PREG</dc:title>
</rdf:Description>
<rdf:Description rdf:about="/Kmtr">
<dcterms:alternative>rate of conversion of CHOC to CHOM</dcterms:alternative>
<dc:title>Kmtr</dc:title>
</rdf:Description>
<rdf:Description rdf:about="/cAMP">
<dcterms:alternative>cyclic AMP</dcterms:alternative>
<dc:title>cAMP</dc:title>
</rdf:Description>
<rdf:Description rdf:about="rdf:#fc21aa07-4c45-47e4-8cce-4f01798bc0e3">
<dc:title>American Journal of Physiology</dc:title>
</rdf:Description>
<rdf:Description rdf:about="/PRO">
<dcterms:alternative>adrenal progesterone</dcterms:alternative>
<dc:title>PRO</dc:title>
</rdf:Description>
<rdf:Description rdf:about="/CORT">
<dcterms:alternative>cortisol</dcterms:alternative>
<dc:title>CORT</dc:title>
</rdf:Description>
<rdf:Description rdf:about="rdf:#74cfeed3-fe5a-4c6d-9146-1f7571651e16">
<rdf:type rdf:resource="http://www.cellml.org/bqs/1.0#Person"/>
<vCard:N rdf:resource="rdf:#c244001b-190d-486a-9115-083809027ffa"/>
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<rdf:Description rdf:about="rdf:#0658c637-7576-42f3-b56a-4de2f45a0b3a">
<dc:creator rdf:resource="rdf:#b8e79f05-e3bf-43fb-a163-5b58bfad67fc"/>
<rdf:value/>
</rdf:Description>
<rdf:Description rdf:about="rdf:#0bbf509a-92bf-4163-9820-8889e7ba7dad">
<vCard:FN>Catherine Lloyd</vCard:FN>
</rdf:Description>
<rdf:Description rdf:about="#dempsher_model_1984">
<dc:title>
Dempsher et al.'s 1984 mathematical model of ACTH-stimulated cortisol secretion.
</dc:title>
<cmeta:bio_entity>cortisol</cmeta:bio_entity>
<cmeta:comment rdf:resource="rdf:#70b63947-bf9a-4ed6-a6a2-7832f4089d49"/>
<bqs:reference rdf:resource="rdf:#0657bf45-30da-4275-9e3a-471729aee554"/>
<bqs:reference rdf:resource="rdf:#df794626-99b8-4fef-b993-418acfbe498e"/>
</rdf:Description>
<rdf:Description rdf:about="/HYPR">
<dcterms:alternative>17alpha hydroxyprogesterone</dcterms:alternative>
<dc:title>HYPR</dc:title>
</rdf:Description>
<rdf:Description rdf:about="rdf:#70b63947-bf9a-4ed6-a6a2-7832f4089d49">
<dc:creator rdf:resource="rdf:#0bbf509a-92bf-4163-9820-8889e7ba7dad"/>
<rdf:value>This is the CellML description of Dempsher et al.'s 1984 mathematical model of ACTH-stimulated cortisol secretion.</rdf:value>
</rdf:Description>
<rdf:Description rdf:about="/CHOC">
<dcterms:alternative>free cytosolic cholesterol</dcterms:alternative>
<dc:title>CHOC</dc:title>
</rdf:Description>
<rdf:Description rdf:about="rdf:#ba482cf9-43bb-4fe6-8010-cbc04509d6fc">
<rdf:type rdf:resource="http://imc.org/vCard/3.0#internet"/>
<rdf:value>c.lloyd@auckland.ac.nz</rdf:value>
</rdf:Description>
<rdf:Description rdf:about="rdf:#d434b2d0-899a-4c31-85af-06cfa2d3324c">
<dcterms:W3CDTF>1984-03-00 00:00</dcterms:W3CDTF>
</rdf:Description>
<rdf:Description rdf:about="rdf:#07756306-fe8b-44b0-8405-812ccd7e61bc">
<vCard:Given>D</vCard:Given>
<vCard:Family>Gann</vCard:Family>
<vCard:Other>S</vCard:Other>
</rdf:Description>
<rdf:Description rdf:about="rdf:#753489a5-3e71-4c1a-81d9-7010f77e05e2">
<rdf:type rdf:resource="http://www.cellml.org/bqs/1.0#Person"/>
<vCard:N rdf:resource="rdf:#4abb09a2-275f-4066-8361-92a3e6f30e88"/>
</rdf:Description>
<rdf:Description rdf:about="/CHOM">
<dcterms:alternative>mitochondrial free cholesterol made available by ACTH</dcterms:alternative>
<dc:title>CHOM</dc:title>
</rdf:Description>
<rdf:Description rdf:about="/CHOL">
<dcterms:alternative>mitochondrial free cholesterol remote from the side chain cleavage enzyme</dcterms:alternative>
<dc:title>CHOL</dc:title>
</rdf:Description>
<rdf:Description rdf:about="/CHON">
<dcterms:alternative>mitochondrial cholesterol close to the side chain cleavage enzyme</dcterms:alternative>
<dc:title>CHON</dc:title>
</rdf:Description>
<rdf:Description rdf:about="rdf:#b8e79f05-e3bf-43fb-a163-5b58bfad67fc">
<vCard:FN/>
</rdf:Description>
<rdf:Description rdf:about="rdf:#49fe8325-99eb-407c-897b-ecc6b816c3aa">
<rdf:type rdf:resource="http://www.cellml.org/bqs/1.0#Person"/>
<vCard:N rdf:resource="rdf:#07756306-fe8b-44b0-8405-812ccd7e61bc"/>
</rdf:Description>
<rdf:Description rdf:about="rdf:#1aa7d171-2410-417a-932d-937315262ab6">
<dc:creator rdf:resource="rdf:#1e1edc53-8ecc-4d3e-9599-b840c42f1d10"/>
<dc:title>A mechanistic model of ACTH-stimulated cortisol secretion</dc:title>
<bqs:volume>246</bqs:volume>
<bqs:first_page>R587</bqs:first_page>
<bqs:Journal rdf:resource="rdf:#fc21aa07-4c45-47e4-8cce-4f01798bc0e3"/>
<dcterms:issued rdf:resource="rdf:#d434b2d0-899a-4c31-85af-06cfa2d3324c"/>
<bqs:last_page>R596</bqs:last_page>
</rdf:Description>
<rdf:Description rdf:about="rdf:#d3b10bee-3260-4bfb-91b9-55d84a2efa68">
<vCard:ORG rdf:resource="rdf:#48a8d31a-49ac-4c39-baf8-aae1b70fbb9f"/>
<vCard:EMAIL rdf:resource="rdf:#ba482cf9-43bb-4fe6-8010-cbc04509d6fc"/>
<vCard:N rdf:resource="rdf:#47070bd7-6102-494f-b48d-67c193ca803d"/>
</rdf:Description>
<rdf:Description rdf:about="rdf:#c244001b-190d-486a-9115-083809027ffa">
<vCard:Given>D</vCard:Given>
<vCard:Family>Dempsher</vCard:Family>
<vCard:Other>P</vCard:Other>
</rdf:Description>
<rdf:Description rdf:about="rdf:#47070bd7-6102-494f-b48d-67c193ca803d">
<vCard:Given>Catherine</vCard:Given>
<vCard:Family>Lloyd</vCard:Family>
<vCard:Other>May</vCard:Other>
</rdf:Description>
<rdf:Description rdf:about="rdf:#22201077-f2e2-4cac-b4d8-4826c632b54d">
<dcterms:W3CDTF>2007-06-28T00:00:00+00:00</dcterms:W3CDTF>
</rdf:Description>
</rdf:RDF>
</model>
