<?xml version="1.0"?>
<!-- FILE : farhy_model_2007.xml
CREATED : 21st June 2007
LAST MODIFIED : 21st 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 Farhy et al.'s 2007 model-projected mechanistic bases for sex differences in growth hormone regulation in humans.
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="farhy_model_2007" name="farhy_model_2007">
<documentation xmlns="http://cellml.org/tmp-documentation">
<article>
<articleinfo>
<title>Model-projected mechanistic bases for sex differences in growth hormone regulation in humans</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 has been curated and is known to run in OpenCell and COR to recreate the published results. The units have been checked and they are consistent. Please note this particular version of the model is specific to females and also GHRH alone is being injected. To simulate the injection of GHS and L-arginine the CellML model will have to be adapted slightly - this is relatively simple to do and will require changing a few initial conditions and parameters according to the description in the original paper.
</para>
</section>
<sect1 id="sec_structure">
<title>Model Structure</title>
<para>
ABSTRACT: Models of physiological systems facilitate rational experimental design, inference, and prediction. A recent construct of regulated growth hormone (GH) secretion interlinks the actions of GH-releasing hormone (GHRH), somatostatin (SRIF), and GH secretagogues (GHS) with GH feedback in the rat (Farhy LS, Veldhuis JD. Am J Physiol Regul Integr Comp Physiol 288: R1649-R1663, 2005). In contrast, no comparable formalism exists to explicate GH dynamics in any other species. The present analyses explore whether a unifying model structure can represent species- and sex-defined distinctions in the human and rodent. The consensus principle that GHRH and GHS synergize in vivo but not in vitro was explicable by assuming that GHS 1) evokes GHRH release from the brain, 2) opposes inhibition by SRIF both in the hypothalamus and on the pituitary gland, and 3) stimulates pituitary GH release directly and additively with GHRH. The gender-selective principle that GH pulses are larger and more irregular in women than men was conferrable by way of 4) higher GHRH potency and 5) greater GHS efficacy. The overall construct predicts GHRH/GHS synergy in the human only in the presence of SRIF when the brain-pituitary nexus is intact, larger and more irregular GH pulses in women, and observed gender differences in feedback by GH and the single and paired actions of GHRH, GHS, and SRIF. The proposed model platform should enhance the framing and interpretation of novel clinical hypotheses and create a basis for interspecies generalization of GH-axis regulation.
</para>
<para>
The complete paper reference is cited below:
</para>
<para>
Model-projected mechanistic bases for sex differences in growth hormone regulation in humans, Leon S. Farhy, Cyril Y. Bowers and Johannes D. Veldhuis, 2006, <emphasis>American Journal of Physiology. Regulatory, Integrative and Comparative Physiology</emphasis>, volume 17, 788-803. <ulink url="http://www.ncbi.nlm.nih.gov/pubmed/17185408">PubMed ID: 17185408</ulink>
</para>
<informalfigure float="0" id="fig_reaction_diagram">
<mediaobject>
<imageobject>
<objectinfo>
<title>model diagram</title>
</objectinfo>
<imagedata fileref="farhy_2007.png"/>
</imageobject>
</mediaobject>
<caption>A schematic diagram of the primary interconnections assumed among growth hormone (GH), growth hormone releasing hormone (GHRH), somatostatin (SRIF) in the periventricular nucleus (SRIF PeV) and arcuate nucleus (SRIF ArC), growth hormone secretagogues (GHS) and GH feedback in the human. The small green arrows denote greater potency (P) or efficacy (E) in women compared with men.</caption>
</informalfigure>
</sect1>
</article>
</documentation>
<units name="ng_ml">
<unit prefix="nano" units="gram"/>
<unit exponent="-1" prefix="milli" units="litre"/>
</units>
<units name="pg_ml">
<unit prefix="pico" units="gram"/>
<unit exponent="-1" prefix="milli" units="litre"/>
</units>
<units name="ng_ml_hr">
<unit units="ng_ml"/>
<unit exponent="-1" units="hour"/>
</units>
<units name="pg_ml_hr">
<unit units="pg_ml"/>
<unit exponent="-1" units="hour"/>
</units>
<units name="hour">
<unit multiplier="3600.0" units="second"/>
</units>
<units name="first_order_rate_constant">
<unit exponent="-1" units="hour"/>
</units>
<component name="environment">
<variable cmeta:id="environment_time" name="time" public_interface="out" units="hour"/>
</component>
<component cmeta:id="GH" name="GH">
<variable cmeta:id="GH_GH" initial_value="0.0" name="GH" public_interface="out" units="ng_ml"/>
<variable initial_value="20.0" name="GHS" public_interface="out" units="dimensionless"/>
<variable initial_value="3.0" name="k1" units="first_order_rate_constant"/>
<variable initial_value="600.0" name="kr1" units="ng_ml_hr"/>
<variable initial_value="357.0" name="t1" units="pg_ml"/>
<variable initial_value="5.0" name="n1" units="dimensionless"/>
<variable initial_value="2.0" name="n2" units="dimensionless"/>
<variable initial_value="2.0" name="g0" units="dimensionless"/>
<variable initial_value="2.9" name="ng0" units="dimensionless"/>
<variable initial_value="200.0" name="tg0" units="dimensionless"/>
<variable initial_value="10.0" name="t2" units="pg_ml"/>
<variable name="SRIF_PeV" public_interface="in" units="pg_ml"/>
<variable name="F1_GHS" public_interface="in" units="dimensionless"/>
<variable name="GHRH" public_interface="in" units="pg_ml"/>
<variable name="ghr_GHRH" public_interface="in" units="pg_ml"/>
<variable name="time" public_interface="in" units="hour"/>
<math xmlns="http://www.w3.org/1998/Math/MathML" id="1">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci> GH </ci>
</apply>
<apply>
<minus/>
<apply>
<times/>
<ci> kr1 </ci>
<apply>
<plus/>
<apply>
<divide/>
<apply>
<power/>
<apply>
<divide/>
<apply>
<plus/>
<ci> GHRH </ci>
<ci> ghr_GHRH </ci>
</apply>
<ci> t1 </ci>
</apply>
<ci> n1 </ci>
</apply>
<apply>
<plus/>
<apply>
<power/>
<apply>
<divide/>
<apply>
<plus/>
<ci> GHRH </ci>
<ci> ghr_GHRH </ci>
</apply>
<ci> t1 </ci>
</apply>
<ci> n1 </ci>
</apply>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless"> 1.0 </cn>
</apply>
</apply>
<apply>
<times/>
<ci> g0 </ci>
<apply>
<divide/>
<apply>
<power/>
<apply>
<divide/>
<ci> GHS </ci>
<ci> tg0 </ci>
</apply>
<ci> ng0 </ci>
</apply>
<apply>
<plus/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless"> 1.0 </cn>
<apply>
<power/>
<apply>
<divide/>
<ci> GHS </ci>
<ci> tg0 </ci>
</apply>
<ci> ng0 </ci>
</apply>
</apply>
</apply>
</apply>
<apply>
<divide/>
<apply>
<plus/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless"> 1.0 </cn>
<ci> F1_GHS </ci>
</apply>
<apply>
<plus/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless"> 1.0 </cn>
<apply>
<power/>
<apply>
<divide/>
<ci> SRIF_PeV </ci>
<ci> t2 </ci>
</apply>
<ci> n2 </ci>
</apply>
<ci> F1_GHS </ci>
</apply>
</apply>
</apply>
</apply>
<apply>
<times/>
<ci> k1 </ci>
<ci> GH </ci>
</apply>
</apply>
</apply>
</math>
</component>
<component cmeta:id="SRIF_PeV" name="SRIF_PeV">
<variable cmeta:id="SRIF_PeV_SRIF_PeV" initial_value="0.0" name="SRIF_PeV" public_interface="out" units="pg_ml"/>
<variable initial_value="25.0" name="k4" units="first_order_rate_constant"/>
<variable initial_value="20400.0" name="kr4" units="pg_ml_hr"/>
<variable initial_value="10.0" name="t5" units="ng_ml"/>
<variable initial_value="2.0" name="n5" units="dimensionless"/>
<variable initial_value="900.0" name="S_basal" units="pg_ml_hr"/>
<variable name="GH" public_interface="in" units="ng_ml"/>
<variable name="time" public_interface="in" units="hour"/>
<math xmlns="http://www.w3.org/1998/Math/MathML" id="2">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci> SRIF_PeV </ci>
</apply>
<apply>
<plus/>
<apply>
<minus/>
<apply>
<times/>
<ci> k4 </ci>
<ci> SRIF_PeV </ci>
</apply>
</apply>
<apply>
<times/>
<ci> kr4 </ci>
<apply>
<divide/>
<apply>
<power/>
<apply>
<divide/>
<ci> GH </ci>
<ci> t5 </ci>
</apply>
<ci> n5 </ci>
</apply>
<apply>
<plus/>
<apply>
<power/>
<apply>
<divide/>
<ci> GH </ci>
<ci> t5 </ci>
</apply>
<ci> n5 </ci>
</apply>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless"> 1.0 </cn>
</apply>
</apply>
</apply>
<ci> S_basal </ci>
</apply>
</apply>
</math>
</component>
<component cmeta:id="SRIF_ArC" name="SRIF_ArC">
<variable cmeta:id="SRIF_ArC_SRIF_ArC" initial_value="0.0" name="SRIF_ArC" public_interface="out" units="pg_ml"/>
<variable initial_value="25.0" name="k2" units="first_order_rate_constant"/>
<variable initial_value="2200.0" name="kr2" units="pg_ml_hr"/>
<variable initial_value="400.0" name="t3" units="pg_ml"/>
<variable initial_value="2.0" name="n3" units="dimensionless"/>
<variable name="GHRH" public_interface="in" units="pg_ml"/>
<variable name="ghr_GHRH" public_interface="in" units="pg_ml"/>
<variable name="time" public_interface="in" units="hour"/>
<math xmlns="http://www.w3.org/1998/Math/MathML" id="3">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci> SRIF_ArC </ci>
</apply>
<apply>
<minus/>
<apply>
<times/>
<ci> kr2 </ci>
<apply>
<divide/>
<apply>
<power/>
<apply>
<divide/>
<apply>
<plus/>
<ci> GHRH </ci>
<ci> ghr_GHRH </ci>
</apply>
<ci> t3 </ci>
</apply>
<ci> n3 </ci>
</apply>
<apply>
<plus/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless"> 1.0 </cn>
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<divide/>
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<plus/>
<ci> GHRH </ci>
<ci> ghr_GHRH </ci>
</apply>
<ci> t3 </ci>
</apply>
<ci> n3 </ci>
</apply>
</apply>
</apply>
</apply>
<apply>
<times/>
<ci> k2 </ci>
<ci> SRIF_ArC </ci>
</apply>
</apply>
</apply>
</math>
</component>
<component cmeta:id="GHRH" name="GHRH">
<variable cmeta:id="GHRH_GHRH" initial_value="0.0" name="GHRH" public_interface="out" units="pg_ml"/>
<variable initial_value="40.0" name="k3" units="first_order_rate_constant"/>
<variable initial_value="63000.0" name="kr3" units="pg_ml_hr"/>
<variable initial_value="28.0" name="t4" units="pg_ml"/>
<variable initial_value="5.0" name="n4" units="dimensionless"/>
<variable name="SRIF_PeV" public_interface="in" units="pg_ml"/>
<variable name="F2_GHS" public_interface="in" units="dimensionless"/>
<variable name="SRIF_ArC" public_interface="in" units="pg_ml"/>
<variable name="ghr_GHRH" public_interface="in" units="pg_ml"/>
<variable name="time" public_interface="in" units="hour"/>
<math xmlns="http://www.w3.org/1998/Math/MathML" id="4">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci> GHRH </ci>
</apply>
<apply>
<minus/>
<apply>
<plus/>
<apply>
<times/>
<ci> kr3 </ci>
<apply>
<divide/>
<apply>
<plus/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless"> 1.0 </cn>
<ci> F2_GHS </ci>
</apply>
<apply>
<plus/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless"> 1.0 </cn>
<apply>
<power/>
<apply>
<divide/>
<apply>
<plus/>
<ci> SRIF_PeV </ci>
<ci> SRIF_ArC </ci>
</apply>
<ci> t4 </ci>
</apply>
<ci> n4 </ci>
</apply>
<ci> F2_GHS </ci>
</apply>
</apply>
</apply>
<apply>
<times/>
<ci> ghr_GHRH </ci>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="first_order_rate_constant"> 1.0 </cn>
</apply>
</apply>
<apply>
<times/>
<ci> k3 </ci>
<ci> GHRH </ci>
</apply>
</apply>
</apply>
</math>
</component>
<component name="F">
<variable cmeta:id="F_F1_GHS" name="F1_GHS" public_interface="out" units="dimensionless"/>
<variable name="F2_GHS" public_interface="out" units="dimensionless"/>
<variable initial_value="90000.0" name="g1" units="dimensionless"/>
<variable initial_value="100.0" name="g2" units="dimensionless"/>
<variable initial_value="390.0" name="tg1" units="dimensionless"/>
<variable initial_value="10000.0" name="tg2" units="dimensionless"/>
<variable initial_value="3.0" name="ng1" units="dimensionless"/>
<variable initial_value="2.0" name="ng2" units="dimensionless"/>
<variable name="GHS" public_interface="in" units="dimensionless"/>
<math xmlns="http://www.w3.org/1998/Math/MathML" id="5">
<apply>
<eq/>
<ci> F1_GHS </ci>
<apply>
<times/>
<ci> g1 </ci>
<apply>
<divide/>
<apply>
<power/>
<apply>
<divide/>
<ci> GHS </ci>
<ci> tg1 </ci>
</apply>
<ci> ng1 </ci>
</apply>
<apply>
<plus/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless"> 1.0 </cn>
<apply>
<power/>
<apply>
<divide/>
<ci> GHS </ci>
<ci> tg1 </ci>
</apply>
<ci> ng1 </ci>
</apply>
</apply>
</apply>
</apply>
</apply>
<apply>
<eq/>
<ci> F2_GHS </ci>
<apply>
<times/>
<ci> g2 </ci>
<apply>
<divide/>
<apply>
<power/>
<apply>
<divide/>
<ci> GHS </ci>
<ci> tg2 </ci>
</apply>
<ci> ng2 </ci>
</apply>
<apply>
<plus/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless"> 1.0 </cn>
<apply>
<power/>
<apply>
<divide/>
<ci> GHS </ci>
<ci> tg2 </ci>
</apply>
<ci> ng2 </ci>
</apply>
</apply>
</apply>
</apply>
</apply>
</math>
</component>
<component cmeta:id="ghr_GHRH" name="ghr_GHRH">
<variable initial_value="0.0" name="ghr_GHRH" public_interface="out" units="pg_ml"/>
<variable name="dghr_GHRH_dt" public_interface="out" units="pg_ml_hr"/>
<variable name="inject" units="pg_ml_hr"/>
<variable initial_value="15.0" name="kghr" units="first_order_rate_constant"/>
<variable initial_value="10000.0" name="C" units="pg_ml_hr"/>
<variable initial_value="2.0" name="onset" units="hour"/>
<variable initial_value="0.2" name="duration" units="hour"/>
<variable name="time" public_interface="in" units="hour"/>
<math xmlns="http://www.w3.org/1998/Math/MathML" id="6">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci> ghr_GHRH </ci>
</apply>
<apply>
<minus/>
<ci> inject </ci>
<apply>
<times/>
<ci> kghr </ci>
<ci> ghr_GHRH </ci>
</apply>
</apply>
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<ci> dghr_GHRH_dt </ci>
<apply>
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<ci> inject </ci>
<apply>
<times/>
<ci> kghr </ci>
<ci> ghr_GHRH </ci>
</apply>
</apply>
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<apply>
<eq/>
<ci> inject </ci>
<piecewise>
<piece>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="pg_ml_hr"> 0.0 </cn>
<apply>
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<ci> time </ci>
<ci> onset </ci>
</apply>
</piece>
<piece>
<ci> C </ci>
<apply>
<and/>
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<geq/>
<ci> time </ci>
<ci> onset </ci>
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<apply>
<leq/>
<ci> time </ci>
<apply>
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<ci> onset </ci>
<ci> duration </ci>
</apply>
</apply>
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<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="pg_ml_hr"> 0.0 </cn>
<apply>
<gt/>
<ci> time </ci>
<apply>
<plus/>
<ci> onset </ci>
<ci> duration </ci>
</apply>
</apply>
</piece>
</piecewise>
</apply>
</math>
</component>
<connection>
<map_components component_1="GHRH" component_2="environment"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
<connection>
<map_components component_1="SRIF_PeV" component_2="environment"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
<connection>
<map_components component_1="SRIF_ArC" component_2="environment"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
<connection>
<map_components component_1="GH" component_2="environment"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
<connection>
<map_components component_1="ghr_GHRH" component_2="environment"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
<connection>
<map_components component_1="GH" component_2="ghr_GHRH"/>
<map_variables variable_1="ghr_GHRH" variable_2="ghr_GHRH"/>
</connection>
<connection>
<map_components component_1="GH" component_2="F"/>
<map_variables variable_1="F1_GHS" variable_2="F1_GHS"/>
<map_variables variable_1="GHS" variable_2="GHS"/>
</connection>
<connection>
<map_components component_1="GH" component_2="GHRH"/>
<map_variables variable_1="GHRH" variable_2="GHRH"/>
</connection>
<connection>
<map_components component_1="GH" component_2="SRIF_PeV"/>
<map_variables variable_1="SRIF_PeV" variable_2="SRIF_PeV"/>
<map_variables variable_1="GH" variable_2="GH"/>
</connection>
<connection>
<map_components component_1="GHRH" component_2="SRIF_PeV"/>
<map_variables variable_1="SRIF_PeV" variable_2="SRIF_PeV"/>
</connection>
<connection>
<map_components component_1="SRIF_ArC" component_2="ghr_GHRH"/>
<map_variables variable_1="ghr_GHRH" variable_2="ghr_GHRH"/>
</connection>
<connection>
<map_components component_1="GHRH" component_2="SRIF_ArC"/>
<map_variables variable_1="SRIF_ArC" variable_2="SRIF_ArC"/>
<map_variables variable_1="GHRH" variable_2="GHRH"/>
</connection>
<connection>
<map_components component_1="GHRH" component_2="F"/>
<map_variables variable_1="F2_GHS" variable_2="F2_GHS"/>
</connection>
<connection>
<map_components component_1="GHRH" component_2="ghr_GHRH"/>
<map_variables variable_1="ghr_GHRH" variable_2="ghr_GHRH"/>
</connection>
<rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
<rdf:Bag rdf:about="rdf:#00df554c-5782-4104-8b08-931a34989464">
<rdf:li>endocrine</rdf:li>
<rdf:li>somatostatin</rdf:li>
<rdf:li>hypothalamus</rdf:li>
<rdf:li>growth hormone releasing hormone</rdf:li>
<rdf:li>growth hormone</rdf:li>
<rdf:li>signal transduction</rdf:li>
</rdf:Bag>
<rdf:Description rdf:about="rdf:#00df554c-5782-4104-8b08-931a34989464"/>
<rdf:Seq rdf:about="rdf:#6ae070c4-ca7d-4239-b9c5-0bf0c97d5bc0">
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<rdf:Description rdf:about="#farhy_model_2007">
<ns7:simulation xmlns:ns7="http://www.cellml.org/metadata/simulation/1.0#" rdf:resource="rdf:#$e1n022"/>
<dc:title xmlns:dc="http://purl.org/dc/elements/1.1/">Farhy et al.'s 2007 model-projected mechanistic bases for sex differences in growth hormone regulation in humans.</dc:title>
<cmeta:bio_entity>hypothalamus</cmeta:bio_entity>
<cmeta:comment rdf:resource="rdf:#14379b56-fdd2-453b-a67b-5abe23bd02e9"/>
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<rdf:value>Fixed a couple of equations, checked and corrected the units such that they are now correct and are consistent, and I added a stimulus to the model (in accordance with the stimulus described in the original publication). The model runs in PCEnv and COR to give the published results, but I can't get the model to oscillate because I haven't been able to include the time delays in the CellML code.</rdf:value>
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