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From damage control to pre-emptive repair. Understanding the role of hypoxia in perioperative liver protection

English title From damage control to pre-emptive repair. Understanding the role of hypoxia in perioperative liver protection
Applicant Beck Schimmer Beatrice
Number 179247
Funding scheme Project funding (Div. I-III)
Research institution Institut für Anästhesiologie Universitätsspital Zürich
Institution of higher education University of Zurich - ZH
Main discipline Pathophysiology
Start/End 01.04.2018 - 31.03.2022
Approved amount 570'000.00
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All Disciplines (2)

Discipline
Pathophysiology
Immunology, Immunopathology

Keywords (5)

HIF-1a; liver regeneration; prolyl hydroxylase inhibitor; organ protection; hypoxia

Lay Summary (German)

Lead
LeadDie Leber ist ein Organ, das nach Entfernen von Gewebe im Gegensatz zu Lunge oder Herz regeneriert. Wie vorgängige Studien unserer Forschungsgruppe gezeigt haben, spielt der Sauerstoffgehalt im Lebergewebe eine Rolle für die Geschwindigkeit des anschliessenden regenerativen Prozesses. Die Entfernung von Lebergewebe und die Veränderung des Blutflusses und die durch die Operation verursachte Entzündung führen zu Wachstum, wobei der Sauerstoffgehalt die Wachstumsgeschwindigkeit steuert. Welche Zellen im Lebergewebe für diese Steuerung verantwortlich sind, ist nicht bekannt.
Lay summary

Titel des Forschungsprojekts

Rolle des Sauerstoffs in der Leberregeneration


Inhalt und Ziele des Forschungsprojekts

Ziel dieses Forschungsprojektes ist es, im Detail die verschiedenen Zelltypen der Leber zu untersuchen und zu analysieren, welche Zellen auf die Veränderung des Sauerstoffgehalts, insbesondere auf die Verringerung des Sauerstoffs reagieren, und wie die verschiedenen Zellen das Sauerstoffsignal untereinander kommunizieren. Dieser Ansatz wird in Zellkultur wie in Tiermodellen untersucht, in denen genetisch bestimmte Defekte im Sauerstoffmesssystem induziert sind.

 

Wissenschaftlicher und gesellschaftlicher Kontext des Forschungsprojekts

Bei Leberschädigung oder chirurgischer Entfernung eines Teils der Leber, hängt die Genesung des Patienten von einer gut ablaufenden Leberregeneration ab. Leberzellen messen Sauerstoff im Geweben durch eine Gruppe von spezifischen Enzymen, die sogenannten Prolylhydroxylasen. Eine Anzahl von Medikamenten steht schon jetzt zur Verfügung, um diese Enzyme zu blockieren und dadurch die Sauerstoffmessung im Gewebe zu manipulieren. Mit diesen Medikamenten kann, wenn die oben genannte Hypothese korrekt ist, Leberwachstum stimuliert werden.

Direct link to Lay Summary Last update: 21.04.2018

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Associated projects

Number Title Start Funding scheme
141216 Immunomodulatory Effects of Trifluorinated Small Molecules: New Therapeutic Opportunities for Ischemia-Reperfusion Injury 01.04.2012 Project funding (Div. I-III)
160283 Does anesthetic management have an impact on circulating tumor cells? 01.04.2015 Project funding (Div. I-III)

Abstract

Ischemia-reperfusion injury is caused by a lack of blood supply to a variety of organs during arterial thrombosis, infarcts and events during surgery and other interventions. It has considerable clinical relevance in perioperative medicine due to its direct impact on clinical outcome. Hypoxia, the temporary lack of oxygen in tissue, may also have a protective effect as shown in ischemic pre- and post-conditioning, where repetitive brief phases of hypoxia are used to mitigate ischemia-reperfusion injury. Ischemic conditioning uses similar signaling pathways as perioperative conditioning with volatile anesthetics, a field in which our group has extensive experience for lung and liver protection. Hypoxia is also well known as trigger for a variety of pathophysiologic processes such as acceleration of cancer growth, development of pulmonary edema and - as was recently shown - liver regeneration.Liver regeneration occurs daily for hemoestasis and especially when the liver is damaged by toxins or ischemia. A good model of liver regeneration is the removal of part of part of the liver, the “partial hepatectomy model”. The liver also increases its regenerative activity when then portal vein blood flow is rerouted to only part of the liver. Portal vein rerouting induces slow liver regeneration, while additional transection of the liver between the portal vein supplied and portal vein deprived sector accelerates this regeneration.Hypoxia and the primary sensors of cell oxygenation prolyl hydroxylases (PHD) have now been shown to be involved in the kinetic rate of liver regenerative processes. Using a partial hepatectomy model, it was demonstrated that PHD knockout mice have accelerated liver regeneration after partial hepatectomy. Also, pharmaceutical interference with oxygen sensing through PHD inhibitors accelerates regeneration model after partial hepatectomy. In our laboratory, we established a rat model of portal vein rerouting and portal vein rerouting plus transection to study mechanisms of rapid and slow liver growth kinetics. There is evidence that hypoxia signaling with hypoxia-inducible factor-1alpha (HIF-1a) may play a central role in the model of rapid hypertrophy. These findings led to the hypothesis that oxygen sensing may control the kinetic rate of regenerative mechanisms in the liver. Goal of this project is to elucidate the effect of hypoxia on proliferation of liver cells in the normal liver and on liver regeneration kinetics after partial portal vein occlusion with transection. The study intends to clarify the cellular crosstalk between hepatocytes and non-parenchymal cell such as hepatic stellate cells, Kupffer cells as well as endothelial cells. We hypothesize that beside hepatocytes hepatic stellate cells and Kupffer cells sense oxygen and play a role in orchestrating and accelerating the process of liver regeneration. In a further step, mice genetically deficient for elements of the HIF1-a pathway will be interrogated in regard to their regenerative kinetics. The project intends to answer the question if the HIF1-a pathway regulates regeneration in the liver.
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