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Projekt
Charakterization of mice lacking functional mitochondrial thioredoxin reductase (TR2): tissue-specific gene targeting
Antragsteller
Dr. Markus Brielmeier
Fachliche Zuordnung
Biochemie
Förderung
Förderung von 2000 bis 2009
Projektkennung
Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 5241270
Glutathione peroxidases (GPxs) and thioredoxin reductases (TRxRs) are selenoproteins playing a crucial role in protecting cells from oxidative damage. There are at least four different GPxs and two different TRxRs in mammalian cells which differ in their site of expression, intracellular localization and/or substrate specificity. GPxs reduce peroxides at the expense of reduced glutathione (GSH). Oxidized glutathione (GSSG) is recycled to GSH through glutathione reductase and NADPH. Phospholipid hydroperoxide glutathione peroxidase (PHGPx) is unique among the glutathione peroxidases for its substrate specificity, its localization at various sites including mitochondria and its high position in the hierarchy of selenoproteins during selenium deprivation. PHGPx is the only glutathione peroxidase that is able to reduce phospholipid hydroperoxides and that also accepts LDL hydroperoxides and cholesterol hydroperoxides as substrates.Thioredoxin reductases, by oxidizing NADPH, regenerate thioredoxins which serve as electron donors in a variety of redox reactions. One of the two known thioredoxin reductases (TRxR2) is localized to mitochondria. The two selenoproteins PHGPx and TRxR2, together with mitochondrial peroxiredoxin and superoxide dismutase, represent the primary line of defense in mitochondria against reactive oxygen intermediates produced by the respiratory chain as a side product of oxygen reduction. To study the expression pattern of PHGPx and TRxR2 at a cellular level and to elucidate their function in vivo, we propose to (i) insert the lacZ gene into the genomic PHGPx and TRxR2 loci and (ii) to knock out the genes in mice. Since PHGPx and TRxR2 might be vitally required, we shall also (iii) generate conditional PHGPx and TRxR2 alleles and shall attempt to knock out the genes in mice in vivo in a tissue specific manner using the CRE-loxP system. We shall investigate the susceptibility of PHGPx and TRxR2 k.o. mice to oxidative stress and the induction of apoptosis.
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