- Author:
- Catherine Lloyd <c.lloyd@auckland.ac.nz>
- Date:
- 2010-02-12 13:17:34+13:00
- Desc:
- Updated documetation and corrected units to get the model now recreating the published results in figure 4.
- Permanent Source URI:
- https://models.cellml.org/workspace/dempsher_gann_phair_1984/rawfile/2ca6eff5a2f314b02b8264725c5f43ef87cc2209/dempsher_gann_phair_1984.cellml
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<title>A mechanistic model of ACTH-stimulated cortisol secretion</title>
<author>
<firstname>Catherine</firstname>
<surname>Lloyd</surname>
<affiliation>
<shortaffil>Auckland Bioengineering Institute, The University of Auckland</shortaffil>
</affiliation>
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<section id="sec_status">
<title>Model Status</title>
<para>
This CellML model runs in both COR and OpenCell to recreate figure 4 from the original paper. All parameter values are set to the same as those in table 1, with the exception of P=0.052 and Q=0.042. There is a small step increase in ACTH concentration from 12pM to 16pM for a duration of 10 minutes with 15 minutes between the two pulses. The units have been checked and they are consistent.
</para>
</section>
<sect1 id="sec_structure">
<title>Model Structure</title>
<para>
ABSTRACT: Adrenal secretory rates of cortisol and arterial concentrations of adrenocorticotropin (ACTH) were measured in conscious trained dogs subjected to intravenous infusion of ACTH. To investigate the causal relation of ACTH to the secretion of cortisol, a mechanistic mathematical model based on current hypotheses of adrenocortical function was constructed and tested. It is widely believed that ACTH stimulates cortisol secretion through adenosine 3',5'-cyclic monophosphate (cAMP), which provides substrate cholesterol by activating cholesterol ester hydrolase and facilitating transport of cholesterol to the side-chain cleavage enzyme. In addition, cholesterol modulates its own synthesis by inhibiting beta-hydroxy-beta-methylglutaryl (HMG)-CoA reductase in the adrenocortical cell. These and other steps in the biosynthetic reaction sequence were described using differential equations subject to the additional constraints imposed by available measurements of intracellular quantities. The resulting model is consistent with many of the known characteristics of the canine adrenal response to ACTH. In this model, steady-state nonlinearities arise from cooperative binding of cAMP to its receptor protein and saturation of mitochondrial pregnenolone transport. The transient response is dominated by a depletable pool of intracellular free cholesterol. Other inferences based on the model are presented, and a quantifiable cellular basis for increased adrenal sensitivity to ACTH is proposed.
</para>
<para>
A mechanistic model of ACTH-stimulated cortisol secretion, D.P. Dempsher, D.S. Gann, and R.D. Phair, 1984,
<emphasis>American Journal of Physiology</emphasis>, 246, R587-R596. <ulink url="http://www.ncbi.nlm.nih.gov/pubmed/6326602">PubMed ID: 6326602</ulink>
</para>
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<caption>Schematic diagram of the model describing the effects of ACTH on cortisol secretion. (note that ECF represents the extracellular fluid).</caption>
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</sect1>
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<connection>
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<connection>
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<connection>
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<connection>
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<connection>
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<connection>
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<connection>
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<connection>
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<connection>
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<connection>
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<connection>
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</connection>
<connection>
<map_components component_2="environment" component_1="CORT"/>
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</connection>
<connection>
<map_components component_2="IS" component_1="cAMP"/>
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</connection>
<connection>
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<connection>
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</connection>
<connection>
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<map_variables variable_2="CHOM" variable_1="CHOM"/>
<map_variables variable_2="CHOC" variable_1="CHOC"/>
</connection>
<connection>
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</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"/>
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</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"/>
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</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:#d7c55d63-141d-4a11-8938-07be8c8a0cb7">
<rdf:li>cortisol</rdf:li>
<rdf:li>HPA axis</rdf:li>
<rdf:li>endocrine</rdf:li>
</rdf:Bag>
<rdf:Seq rdf:about="rdf:#a4d925c2-b101-406f-b1dc-aa6211b52eda">
<rdf:li rdf:resource="rdf:#02d23f7a-075f-4b83-b36d-d7cf168d6ea6"/>
<rdf:li rdf:resource="rdf:#594c3491-ad57-40cf-aafa-81dfb06012d1"/>
<rdf:li rdf:resource="rdf:#4bed82da-10ad-41c9-adbf-f9c32ccd872e"/>
</rdf:Seq>
<rdf:Description rdf:about="rdf:#95863279-64bc-473f-a01c-e5c695e29c7d">
<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:#7ebd2478-51d9-48d2-bf07-664fc00266ea">
<vCard:ORG rdf:resource="rdf:#a3e955af-d295-435d-9a04-98c4d4b7d2fd"/>
<vCard:EMAIL rdf:resource="rdf:#95863279-64bc-473f-a01c-e5c695e29c7d"/>
<vCard:N rdf:resource="rdf:#3f0e9044-0db6-4831-9381-91fb8593d8fd"/>
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<dcterms:modified rdf:resource="rdf:#b60dd978-75a6-4700-8a10-6016836a5188"/>
<rdf:value>The model has been curated further. Using COR the units were made consistent and one equation was fixed. The model still can't perfectly recreate the published results in COR though. I'm waiting for Alan to fix a bug in COR and then I'll try again.</rdf:value>
<cmeta:modifier rdf:resource="rdf:#d6d1654d-792a-49b6-b163-eae8ed1fc376"/>
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<rdf:Description rdf:about="rdf:#fcea56f3-b232-4dae-98ad-b78ea38d7f9e">
<dc:creator rdf:resource="rdf:#d43c8b12-aba6-40fb-b46c-e207abd4fec4"/>
<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="#IS">
<dcterms:alternative>intracellular signal</dcterms:alternative>
<dc:title>IS</dc:title>
</rdf:Description>
<rdf:Description rdf:about="#HYPR">
<dcterms:alternative>17alpha hydroxyprogesterone</dcterms:alternative>
<dc:title>HYPR</dc:title>
</rdf:Description>
<rdf:Description rdf:about="">
<dc:publisher>The University of Auckland, Auckland Bioengineering Institute</dc:publisher>
<cmeta:comment rdf:resource="rdf:#ac55def9-9839-4c88-ac6d-14f1f4dc2eef"/>
<dcterms:created rdf:resource="rdf:#4948f6f6-ad09-436e-98ee-8d5c3c2365fa"/>
<dc:creator rdf:resource="rdf:#7ebd2478-51d9-48d2-bf07-664fc00266ea"/>
<cmeta:modification rdf:resource="rdf:#6b2f481e-3d84-4c31-b2b5-e3e3e4369017"/>
<cmeta:modification rdf:resource="rdf:#d357af8c-2834-4bd6-a1d7-9fa581858722"/>
</rdf:Description>
<rdf:Description rdf:about="rdf:#17ff97a0-6efa-434b-8d52-7d4175643f18">
<dcterms:W3CDTF>1984-00-00 00:00</dcterms:W3CDTF>
</rdf:Description>
<rdf:Description rdf:about="rdf:#0f509d5b-cbba-41e4-a713-70e37d13cfe8">
<dc:title>American Journal of Physiology</dc:title>
</rdf:Description>
<rdf:Description rdf:about="rdf:#ba223a49-ea5c-4c85-96f7-96dc3fb72691">
<vCard:Given>D</vCard:Given>
<vCard:Family>Dempsher</vCard:Family>
<vCard:Other>P</vCard:Other>
</rdf:Description>
<rdf:Description rdf:about="rdf:#4ec0e440-dbab-47f8-a81f-e03b1b5e8333">
<vCard:N rdf:resource="rdf:#60ab2c1b-a832-48ab-9c1f-7266592e897b"/>
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<rdf:Description rdf:about="rdf:#$hD.6n1">
<ns7:endingValue>100</ns7:endingValue>
<ns7:nonstandard-pointDensity>10000</ns7:nonstandard-pointDensity>
<ns7:maximumStepSize>0.01</ns7:maximumStepSize>
</rdf:Description>
<rdf:Description rdf:about="rdf:#24cbbbda-149d-43c3-b7eb-554e4357cc75">
<vCard:Given>R</vCard:Given>
<vCard:Family>Phair</vCard:Family>
<vCard:Other>D</vCard:Other>
</rdf:Description>
<rdf:Description rdf:about="#CORT">
<dcterms:alternative>cortisol</dcterms:alternative>
<dc:title>CORT</dc:title>
</rdf:Description>
<rdf:Description rdf:about="rdf:#02d23f7a-075f-4b83-b36d-d7cf168d6ea6">
<rdf:type rdf:resource="http://www.cellml.org/bqs/1.0#Person"/>
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<rdf:Description rdf:about="rdf:#76b454ef-9b0c-4d9f-af4f-30ae6e15fe1d">
<vCard:Given>D</vCard:Given>
<vCard:Family>Gann</vCard:Family>
<vCard:Other>S</vCard:Other>
</rdf:Description>
<rdf:Description rdf:about="#PRO">
<dcterms:alternative>adrenal progesterone</dcterms:alternative>
<dc:title>PRO</dc:title>
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<rdf:Description rdf:about="rdf:#6b2f481e-3d84-4c31-b2b5-e3e3e4369017">
<dcterms:modified rdf:resource="rdf:#3428c244-c9b5-47d1-ba16-f5842598c0bb"/>
<rdf:value>Change in simulation metadata - added cmeta:id's to some variables</rdf:value>
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<rdf:rest rdf:resource="http://www.w3.org/1999/02/22-rdf-syntax-ns#nil"/>
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<rdf:Description rdf:about="#PREG">
<dcterms:alternative>mitochondrial pregnolone</dcterms:alternative>
<dc:title>PREG</dc:title>
</rdf:Description>
<rdf:Description rdf:about="rdf:#d43c8b12-aba6-40fb-b46c-e207abd4fec4">
<vCard:FN>Catherine Lloyd</vCard:FN>
</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="rdf:#a8233bc4-89cb-4196-8ee0-f85907715798">
<bqs:subject_type>keyword</bqs:subject_type>
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<rdf:Description rdf:about="#dempsher_model_1984">
<ns7:simulation rdf:resource="rdf:#$fD.6n1"/>
<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:#fcea56f3-b232-4dae-98ad-b78ea38d7f9e"/>
<bqs:reference rdf:resource="rdf:#084a4476-0d34-4272-be7d-10f458325c15"/>
<bqs:reference rdf:resource="rdf:#64998e2d-6349-492f-a04a-4e18f11a9781"/>
</rdf:Description>
<rdf:Description rdf:about="rdf:#ac55def9-9839-4c88-ac6d-14f1f4dc2eef">
<dc:creator rdf:resource="rdf:#659a95e5-73f7-406e-84ff-f560d9cece7d"/>
<rdf:value>The model has been curated further. Using COR the units were made consistent and one equation was fixed. The model still can't perfectly recreate the published results though. I'm waiting for Alan to fix a bug in COR and then I'll try again.</rdf:value>
</rdf:Description>
<rdf:Description rdf:about="rdf:#64998e2d-6349-492f-a04a-4e18f11a9781">
<bqs:Pubmed_id>6326602</bqs:Pubmed_id>
<bqs:JournalArticle rdf:resource="rdf:#925ab9e0-f346-490f-9638-d083da3f446f"/>
</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="#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:#4bed82da-10ad-41c9-adbf-f9c32ccd872e">
<rdf:type rdf:resource="http://www.cellml.org/bqs/1.0#Person"/>
<vCard:N rdf:resource="rdf:#24cbbbda-149d-43c3-b7eb-554e4357cc75"/>
</rdf:Description>
<rdf:Description rdf:about="rdf:#7a7ea219-4d7f-4e11-a5b3-8ec76052dc6b">
<vCard:Given>Catherine</vCard:Given>
<vCard:Family>Lloyd</vCard:Family>
<vCard:Other>May</vCard:Other>
</rdf:Description>
<rdf:Description rdf:about="rdf:#a3e955af-d295-435d-9a04-98c4d4b7d2fd">
<vCard:Orgname>The University of Auckland</vCard:Orgname>
<vCard:Orgunit>Auckland Bioengineering Institute</vCard:Orgunit>
</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:#b60dd978-75a6-4700-8a10-6016836a5188">
<dcterms:W3CDTF>2007-09-02T11:49:51+12:00</dcterms:W3CDTF>
</rdf:Description>
<rdf:Description rdf:about="rdf:#4948f6f6-ad09-436e-98ee-8d5c3c2365fa">
<dcterms:W3CDTF>2007-06-28T00:00:00+00:00</dcterms:W3CDTF>
</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:#925ab9e0-f346-490f-9638-d083da3f446f">
<dc:creator rdf:resource="rdf:#a4d925c2-b101-406f-b1dc-aa6211b52eda"/>
<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:#0f509d5b-cbba-41e4-a713-70e37d13cfe8"/>
<dcterms:issued rdf:resource="rdf:#17ff97a0-6efa-434b-8d52-7d4175643f18"/>
<bqs:last_page>R596</bqs:last_page>
</rdf:Description>
<rdf:Description rdf:about="rdf:#60ab2c1b-a832-48ab-9c1f-7266592e897b">
<vCard:Given>Tiwari</vCard:Given>
<vCard:Family>Abhishek</vCard:Family>
</rdf:Description>
<rdf:Description rdf:about="rdf:#3f0e9044-0db6-4831-9381-91fb8593d8fd">
<vCard:Given>Catherine</vCard:Given>
<vCard:Family>Lloyd</vCard:Family>
<vCard:Other>May</vCard:Other>
</rdf:Description>
<rdf:Description rdf:about="rdf:#659a95e5-73f7-406e-84ff-f560d9cece7d">
<vCard:FN>Catherine Lloyd</vCard:FN>
</rdf:Description>
<rdf:Description rdf:about="rdf:#084a4476-0d34-4272-be7d-10f458325c15">
<dc:subject rdf:resource="rdf:#a8233bc4-89cb-4196-8ee0-f85907715798"/>
</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:#3428c244-c9b5-47d1-ba16-f5842598c0bb">
<dcterms:W3CDTF>2008-11-19T12:09:24+13:00</dcterms:W3CDTF>
</rdf:Description>
<rdf:Description rdf:about="rdf:#$fD.6n1">
<ns7:boundIntervals rdf:resource="rdf:#$gD.6n1"/>
</rdf:Description>
</rdf:RDF>
</model>
