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                <term xml:lang="en">Systems biology</term>
                <term xml:lang="en">Ammonia</term>
                <term xml:lang="en">Spatio-temporal model</term>
                <term xml:lang="en">Liver damage</term>
                <term xml:lang="en">Liver regeneration</term>
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              <p>Background &amp;amp; aims: Recently, spatial-temporal/metabolic mathematical models have been established that allow the simulation of metabolic processes in tissues. We applied these models to decipher ammonia detoxification mechanisms in the liver.Methods: An integrated metabolic-spatial-temporal model was used to generate hypotheses of ammonia metabolism. Predicted mechanisms were validated using time resolved analyses of nitrogen metabolism, activity analyses, immunostaining and gene expression after induction of liver damage in mice. Moreover, blood from the portal vein, liver vein and mixed venous blood was analyzed in a time dependent manner.Results: Modeling revealed an underestimation of ammonia consumption after liver damage when only the currently established mechanisms of ammonia detoxification were simulated. By iterative cycles of modeling and experiments the reductive amidation of alpha-ketoglutarate (α-KG) via glutamate dehydrogenase (GDH) was identified as the lacking component. GDH is released from damaged hepatocytes into the blood where it consumes ammonia to generate glutamate, thereby providing systemic protection against hyperammonemia. This mechanism was exploited therapeutically in a mouse model of hyperammonemia by injecting GDH together with optimized doses of co-factors. Intravenous injection of GDH (720 U/kg), α-KG (280 mg/kg) and NADPH (180 mg/kg) reduced the elevated blood ammonia concentrations (&amp;gt;200 μM) to levels close to normal within only 15 min.Conclusion: If successfully translated to patients the GDH-based therapy might provide a less aggressive therapeutic alternative for patients with severe hyperammonemia.</p>
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              <addrLine>Auerbach Str. 11270376 Stuttgart</addrLine>
              <country key="DE"/>
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            <ref type="url">http://www.fightingdrugfailure.net/fightingdrugfailure/partner-sites/dr-margarete-fischer-bosch-institute-of-clinical-pharmacology-ikp.html</ref>
          </desc>
        </org>
        <org type="institution" xml:id="struct-209475" status="VALID">
          <orgName>Eberhard Karls Universität Tübingen =  University of Tübingen</orgName>
          <desc>
            <address>
              <addrLine>Geschwister-Scholl-Platz 72074 Tübingen</addrLine>
              <country key="DE"/>
            </address>
            <ref type="url">http://www.uni-tuebingen.de/</ref>
          </desc>
        </org>
        <org type="laboratory" xml:id="struct-450026" status="VALID">
          <orgName>Institut für Biochemie [Leipzig]</orgName>
          <desc>
            <address>
              <addrLine>Brüderstraße 34D-04103 Leipzig</addrLine>
              <country key="DE"/>
            </address>
            <ref type="url">http://www.biochemie.uni-leipzig.de/default_en.asp</ref>
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        </org>
        <org type="laboratory" xml:id="struct-207458" status="VALID">
          <orgName>Center for Molecular Medicine [Cologne]</orgName>
          <orgName type="acronym">CMMC</orgName>
          <desc>
            <address>
              <addrLine>Robert Koch Str. 21 D-50931 Köln</addrLine>
              <country key="DE"/>
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            <ref type="url">http://www.zmmk.uni-koeln.de/</ref>
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          <listRelation>
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        </org>
        <org type="laboratory" xml:id="struct-411236" status="VALID">
          <orgName>Computational Systems Biology [Leverkusen]</orgName>
          <desc>
            <address>
              <addrLine>CHEMPARK Building B10651368 Leverkusen</addrLine>
              <country key="DE"/>
            </address>
            <ref type="url">http://www.systems-biology.com/nc/contact.html</ref>
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        </org>
        <org type="department" xml:id="struct-109409" status="VALID">
          <orgName>Department of Gastroenterology, Hepatology and Infectiology [Düsseldorf]</orgName>
          <desc>
            <address>
              <addrLine>Moorenstr. 540225 Düsseldorf</addrLine>
              <country key="DE"/>
            </address>
            <ref type="url">http://www.uniklinik-duesseldorf.de/en/unternehmen/kliniken/department-of-gastroenterology-hepatology-and-infectiology/</ref>
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          <listRelation>
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        </org>
        <org type="laboratory" xml:id="struct-450022" status="VALID">
          <orgName>Faculty of Veterinary Medicine [Qena]</orgName>
          <desc>
            <address>
              <addrLine>83523 Qena</addrLine>
              <country key="EG"/>
            </address>
            <ref type="url">http://www.svu.edu.eg/faculties/veter_medicine_e/index.htm</ref>
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        <org type="institution" xml:id="struct-450021" status="VALID">
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          <idno type="ROR">https://ror.org/00jxshx33</idno>
          <idno type="Wikidata">Q7568730</idno>
          <orgName>South Valley University [Egypt] =  جامعة جنوب الوادي</orgName>
          <orgName type="acronym">SVU</orgName>
          <date type="start">1995-01-01</date>
          <desc>
            <address>
              <addrLine>83523 Qena, Egypt</addrLine>
              <country key="EG"/>
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            <ref type="url">http://www.svu.edu.eg/</ref>
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        <org type="institution" xml:id="struct-133089" status="VALID">
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          <orgName type="acronym">TU</orgName>
          <desc>
            <address>
              <addrLine>August-Schmidt-Straße 1, 44227 Dortmund</addrLine>
              <country key="DE"/>
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            <ref type="url">https://www.tu-dortmund.de/</ref>
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          <idno type="RNSR">199712644L</idno>
          <orgName>Laboratoire Jacques-Louis Lions</orgName>
          <orgName type="acronym">LJLL</orgName>
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            <address>
              <addrLine>Université Pierre et Marie Curie, Boîte courrier 187 - 75252 Paris Cedex 05</addrLine>
              <country key="FR"/>
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            <ref type="url">https://www.ljll.math.upmc.fr</ref>
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          <idno type="ROR">https://ror.org/02en5vm52</idno>
          <orgName>Université Pierre et Marie Curie - Paris 6</orgName>
          <orgName type="acronym">UPMC</orgName>
          <date type="end">2017-12-31</date>
          <desc>
            <address>
              <addrLine>4 place Jussieu - 75005 Paris</addrLine>
              <country key="FR"/>
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            <ref type="url">http://www.upmc.fr/</ref>
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          <idno type="ISNI">0000000121514068</idno>
          <idno type="ROR">https://ror.org/02n7qrg46</idno>
          <orgName>Université Paris Diderot - Paris 7</orgName>
          <orgName type="acronym">UPD7</orgName>
          <date type="end">2019-12-31</date>
          <desc>
            <address>
              <addrLine>5 rue Thomas-Mann - 75205 Paris cedex 13</addrLine>
              <country key="FR"/>
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            <ref type="url">http://www.univ-paris-diderot.fr</ref>
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          <idno type="ISNI">0000000122597504</idno>
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          <orgName>Centre National de la Recherche Scientifique</orgName>
          <orgName type="acronym">CNRS</orgName>
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          <desc>
            <address>
              <country key="FR"/>
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            <ref type="url">https://www.cnrs.fr/</ref>
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        </org>
        <org type="laboratory" xml:id="struct-86790" status="OLD">
          <orgName>Inria Paris-Rocquencourt</orgName>
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            <address>
              <addrLine>INRIA Rocquencourt : Domaine de Voluceau, Rocquencourt B.P. 105 78153 le Chesnay Cedex</addrLine>
              <country key="FR"/>
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            <ref type="url">http://www.inria.fr/centre/paris-rocquencourt</ref>
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        <org type="institution" xml:id="struct-300009" status="VALID">
          <idno type="ROR">https://ror.org/02kvxyf05</idno>
          <orgName>Institut National de Recherche en Informatique et en Automatique</orgName>
          <orgName type="acronym">Inria</orgName>
          <desc>
            <address>
              <addrLine>Domaine de VoluceauRocquencourt - BP 10578153 Le Chesnay Cedex</addrLine>
              <country key="FR"/>
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            <ref type="url">http://www.inria.fr/en/</ref>
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        </org>
        <org type="institution" xml:id="struct-562203" status="VALID">
          <idno type="ROR">https://ror.org/03s7gtk40</idno>
          <orgName>Leipzig University / Universität Leipzig</orgName>
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            <address>
              <addrLine>Augustusplatz 10, 04109 Leipzig, Allemagne</addrLine>
              <country key="DE"/>
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        </org>
        <org type="institution" xml:id="struct-463785" status="VALID">
          <idno type="ROR">https://ror.org/00rcxh774</idno>
          <orgName>Universität zu Köln = University of Cologne</orgName>
          <date type="start">2016-09-14</date>
          <desc>
            <address>
              <addrLine>Albertus-Magnus-Platz, 50923 Köln</addrLine>
              <country key="DE"/>
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            <ref type="url">https://www.uni-koeln.de</ref>
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        </org>
        <org type="institution" xml:id="struct-450082" status="VALID">
          <orgName>Bayer Technology Services [Leverkusen]</orgName>
          <desc>
            <address>
              <addrLine>CHEMPARK Building B10651368 Leverkusen</addrLine>
              <country key="DE"/>
            </address>
            <ref type="url">http://www.systems-biology.com/</ref>
          </desc>
        </org>
        <org type="institution" xml:id="struct-335120" status="VALID">
          <orgName>Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf]</orgName>
          <date type="start">1965-01-01</date>
          <desc>
            <address>
              <addrLine>Universitätsstr. 140225 Düsseldorf</addrLine>
              <country key="DE"/>
            </address>
            <ref type="url">https://www.uni-duesseldorf.de</ref>
          </desc>
        </org>
      </listOrg>
    </back>
  </text>
</TEI>