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In-depth analysis of pharmacological PHD-inhibitors for the prevention of ischemic liver injuries PDF Print E-mail
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Saturday, 24 April 2010 20:46

Fachgebiete: Biologie Pharmazie
Thema: Diplomarbeit: In-depth analysis of pharmacological PHD-inhibitors for the prevention of ischemic liver injuries
Ansprechpartner: Herr Martin Mollenhauer
Antwort an: This e-mail address is being protected from spambots. You need JavaScript enabled to view it
Institution: Fakultät für Biowissenschaften
Ort: 69120 Heidelberg, INF 110

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Cellular adaption mechanisms during oxygen deficiency are determined by Hypoxia Inducible Transcription factors (HIF). Under normoxic conditions three recently identified HIF- prolyl-hydroxylases (PHD1, PHD2 and PHD3) trigger the inactivation of HIF.
In vivo studies have demonstrated that loss of PHD1, but not PHD2 or PHD3, leads to an adaption of the mitochondrial energy metabolism, which protects the skeletal musculature of PHD1-deficient mice from oxidative stress and ischemic necrosis.
Importantly, current observations revealed a striking resistance of the liver tissue of (PHD1-/-) mice against oxidative stress caused by ischemia/reperfusion (I/R). This tissue protection is also existent after inhibition of PHD1 by pharmacological agents in WT mice. Since PHD inhibitors work via a competitive inhibition on the active site of the hydroxilases, they are not specific for a certain PHD-enzyme. Therefore further investigations are needed to test whether these agents also affect the organism by inhibiting the PHD2 and PHD3 enzymes.
The first aim of this Master-/ Diploma thesis is to identify the specificity of three PHD inhibitors on PHD1 ex vivo in murine primary hepatocytes and in vitro in an immortalized AML12 hepatic cell line. Furthermore, new molecular targets shall be identified, that are specifically modulated by pharmacological PHD-inhibition in order to prevent oxidative I/R liver injury.


Methoden:
WST-1-, BrdU-assays, toxicity- and apoptotic assays, expression analyses by quantitative RT-PCR, knock-down RNAi techniques and histological analyses

Anfangsdatum: 1. Oktober 2009

geschätzte Dauer: 6 Monate

Bezahlung: -

*http://jobs.uni-hd.de
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