<?xml version='1.0' encoding='utf-8'?>
<!-- FILE : gonzalezheydrich_model_1994.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 Gonzalez-Heydrich et al.'s 1994 mathematical model of the HPA axis.
CHANGES:
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<documentation xmlns="http://cellml.org/tmp-documentation">
<article>
<articleinfo>
<title>A computer simulation of the hypothalamic-pituitary-adrenal axis</title>
<author>
<firstname>Catherine</firstname>
<surname>Lloyd</surname>
<affiliation>
<shortaffil>Auckland Bioengineering Institute, The University of Auckland</shortaffil>
</affiliation>
</author>
</articleinfo>
<section id="sec_status">
<title>Model Status</title>
<para>
This model runs in OpenCell and COR. The units have been checked and they are consistent. Please note this CellML translation was based on a an online version of the original paper - a version which contains more defined parameter values than the paper linked to from PubMed (<ulink url="http://chip.org/projects/hpa/paper-hpa.html">the more detailed description</ulink>). Also there is a typo in this description in the ACTH Module. There should be a minus sign rather than a plus sign infront of (k4*[CRH]+k5) (We thank the original model author for highlighting this). The correct equation is as follows: d[ACTH]/dt = k4*[CRH]+k5 - k6*[ACTH]- (k4*[CRH]+k5)*Imax*[cortisol]/(Kd+[cortisol]). Unfortunately there are no published figures of the results of the original model so we cannot confirm the CellML translation recreates the original published results.
</para>
</section>
<sect1 id="sec_structure">
<title>Model Structure</title>
<para>
ABSTRACT: This paper describes the construction of a computer model that simulates the hypothalamic-pituitary-adrenal axis (HPA axis) regulation of cortisol production. It is presented to illustrate the process of physiological modeling using standard "off the shelf" technologies. The model simulates components of the HPA axis involved in the continuous secretion and elimination of cortisol, adrenocorticotropin (ACTH), and corticotropin releasing hormone (CRH). The physiological relations of these component pieces were modeled based on the current knowledge of their functioning. Rate constants, half lives, and receptor affinities were assigned values derived from the experimental literature. At its current level of development the model is able to accurately simulate the timing, magnitude and decay of the ACTH and cortisol concentration peaks resulting from the ovine-CRH stimulation test in normal and hypercortisolemic patients. The model will be used to predict the effects of lesions in different components of the HPA axis on the time course of cortisol and ACTH levels. We plan to use the model to explore the experimental conditions required to distinguish mechanisms underlying various disorders of the HPA axis, particularly depression. Efforts are currently underway to validate the model for a large variety of normal and pathological perturbations of the HPA axis.
</para>
<para>
The complete paper reference is cited below:
</para>
<para>
A computer simulation of the hypothalamic-pituitary-adrenal axis, J. Gonzalez-Heydrich, R.J. Steingard and I Kohane, 1994, <emphasis>Eighteenth Annual Proceedings of the Symposium for Computer Applications in Medical Care</emphasis>, pp1010. <ulink url="http://www.ncbi.nlm.nih.gov/pubmed/7949852">PubMed ID: 7949852</ulink>
</para>
<informalfigure float="0" id="fig_reaction_diagram">
<mediaobject>
<imageobject>
<objectinfo>
<title>model diagram</title>
</objectinfo>
<imagedata fileref="gonzalezheidrich_1994.png"/>
</imageobject>
</mediaobject>
<caption>Schematic diagram of the self-regulatory system for corticol secretion. CRH represents corticotropin-releasing hormone, and ACTH is adrenocorticotropic hormone.</caption>
</informalfigure>
</sect1>
</article>
</documentation>
<units name="mcg_ml">
<unit units="gram" prefix="micro"/>
<unit units="litre" prefix="milli" exponent="-1"/>
</units>
<units name="minute">
<unit units="second" multiplier="60.0"/>
</units>
<units name="flux">
<unit units="mcg_ml"/>
<unit units="minute" exponent="-1"/>
</units>
<units name="first_order_rate_constant">
<unit units="minute" exponent="-1"/>
</units>
<component name="environment">
<variable units="minute" public_interface="out" name="time"/>
</component>
<component name="cortisol">
<variable units="mcg_ml" public_interface="out" name="cortisol" initial_value="0.0"/>
<variable units="first_order_rate_constant" name="k1" initial_value="5E5"/>
<variable units="flux" name="k2" initial_value="0.01"/>
<variable units="first_order_rate_constant" name="k3" initial_value="0.01"/>
<variable units="mcg_ml" public_interface="in" name="ACTH"/>
<variable units="minute" public_interface="in" name="time"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci> cortisol </ci>
</apply>
<apply>
<minus/>
<apply>
<plus/>
<apply>
<times/>
<ci> k1 </ci>
<ci> ACTH </ci>
</apply>
<ci> k2 </ci>
</apply>
<apply>
<times/>
<ci> k3 </ci>
<ci> cortisol </ci>
</apply>
</apply>
</apply>
</math>
</component>
<component cmeta:id="ACTH" name="ACTH">
<variable units="mcg_ml" public_interface="out" name="ACTH" initial_value="0.0"/>
<variable units="first_order_rate_constant" name="k4" initial_value="10.0"/>
<variable units="flux" name="k5" initial_value="4E-3"/>
<variable units="first_order_rate_constant" name="k6" initial_value="0.035"/>
<variable units="mcg_ml" name="Kd" initial_value="0.004"/>
<variable units="dimensionless" name="Imax" initial_value="0.99"/>
<variable units="mcg_ml" public_interface="in" name="CRH"/>
<variable units="mcg_ml" public_interface="in" name="cortisol"/>
<variable units="minute" public_interface="in" name="time"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci> ACTH </ci>
</apply>
<apply>
<minus/>
<apply>
<plus/>
<apply>
<times/>
<ci> k4 </ci>
<ci> CRH </ci>
</apply>
<ci> k5 </ci>
</apply>
<apply>
<plus/>
<apply>
<times/>
<ci> k6 </ci>
<ci> ACTH </ci>
</apply>
<apply>
<times/>
<apply>
<plus/>
<apply>
<times/>
<ci> k4 </ci>
<ci> CRH </ci>
</apply>
<ci> k5 </ci>
</apply>
<apply>
<divide/>
<apply>
<times/>
<ci> Imax </ci>
<ci> cortisol </ci>
</apply>
<apply>
<plus/>
<ci> Kd </ci>
<ci> cortisol </ci>
</apply>
</apply>
</apply>
</apply>
</apply>
</apply>
</math>
</component>
<component cmeta:id="CRH" name="CRH">
<variable units="mcg_ml" public_interface="out" name="CRH" initial_value="50.0"/>
<variable units="flux" name="k7" initial_value="1E-6"/>
<variable units="first_order_rate_constant" name="k8" initial_value="0.01"/>
<variable units="flux" name="pulse" initial_value="50.0"/>
<variable units="minute" public_interface="in" name="time"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci> CRH </ci>
</apply>
<apply>
<minus/>
<apply>
<plus/>
<ci> pulse </ci>
<ci> k7 </ci>
</apply>
<apply>
<times/>
<ci> k8 </ci>
<ci> CRH </ci>
</apply>
</apply>
</apply>
</math>
</component>
<connection>
<map_components component_2="environment" component_1="cortisol"/>
<map_variables variable_2="time" variable_1="time"/>
</connection>
<connection>
<map_components component_2="environment" component_1="ACTH"/>
<map_variables variable_2="time" variable_1="time"/>
</connection>
<connection>
<map_components component_2="environment" component_1="CRH"/>
<map_variables variable_2="time" variable_1="time"/>
</connection>
<connection>
<map_components component_2="ACTH" component_1="cortisol"/>
<map_variables variable_2="cortisol" variable_1="cortisol"/>
<map_variables variable_2="ACTH" variable_1="ACTH"/>
</connection>
<connection>
<map_components component_2="ACTH" component_1="CRH"/>
<map_variables variable_2="CRH" variable_1="CRH"/>
</connection>
<rdf:RDF>
<rdf:Bag rdf:about="rdf:#6aa7b954-3a56-40d5-bacd-0bb38097d15c">
<rdf:li>endocrine</rdf:li>
<rdf:li>hpa axis</rdf:li>
<rdf:li>HPA axis</rdf:li>
<rdf:li>cortisol</rdf:li>
</rdf:Bag>
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<rdf:Description rdf:about="">
<dc:publisher>The University of Auckland, Auckland Bioengineering Institute</dc:publisher>
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<vCard:FN>Catherine Lloyd</vCard:FN>
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<vCard:Given>R</vCard:Given>
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<vCard:Given>I</vCard:Given>
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<rdf:value>The model has been checked in COR too. The units have been corrected and are consistent. The model runs in PCEnv but I'm not sure if it recreates the original results because the paper doesn't include any! Also, I think there may be a typo in the paper's equation to calculate ACTH - it looks a bit odd.</rdf:value>
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<vCard:Given>Catherine</vCard:Given>
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<dc:creator rdf:resource="rdf:#068b2416-0341-4959-898c-6d844493199b"/>
<rdf:value>The model has been checked in COR too. The units have been corrected and are consistent. The model runs in PCEnv but I'm not sure if it recreates the original results because the paper doesn't include any! Also, I think there may be a typo in the paper's equation to calculate ACTH - it looks a bit odd.</rdf:value>
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<dcterms:W3CDTF>1994-00-00 00:00</dcterms:W3CDTF>
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<vCard:Given>Catherine</vCard:Given>
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<vCard:Orgname>The University of Auckland</vCard:Orgname>
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<dcterms:W3CDTF>2007-09-02T16:04:16+12:00</dcterms:W3CDTF>
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<rdf:Description rdf:about="rdf:#bb39b022-dd12-4927-8371-57d7e5e27782">
<dc:title>Eighteenth Annual Proceedings of the Symposium for Computer Applications in Medical Care</dc:title>
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<dcterms:W3CDTF>2007-06-29T00:00:00+00:00</dcterms:W3CDTF>
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<dc:title>A computer simulation of the hypothalamic-pituitary-adrenal axis</dc:title>
<bqs:volume/>
<bqs:first_page>1010</bqs:first_page>
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<rdf:Description rdf:about="#gonzalezheydrich_model_1994">
<dc:title>
Gonzalez-Heydrich et al.'s 1994 mathematical model of the HPA axis.
</dc:title>
<cmeta:bio_entity>cortisol</cmeta:bio_entity>
<cmeta:comment rdf:resource="rdf:#54258794-b4a4-4d71-929c-166791385a26"/>
<bqs:reference rdf:resource="rdf:#176ac537-a60d-4f4c-a36d-ffa46e104b9e"/>
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<rdf:Description rdf:about="#CRH">
<dcterms:alternative>corticotropin releasing hormone</dcterms:alternative>
<dc:title>CRH</dc:title>
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<vCard:FN>Catherine Lloyd</vCard:FN>
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<rdf:Description rdf:about="#ACTH">
<dcterms:alternative>acetylcholine</dcterms:alternative>
<dc:title>ACTH</dc:title>
</rdf:Description>
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</model>
