EURON and THEME joint PhD meeting

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56 EURON and THEME joint meeting 2011 Functions of fatty acid 2-hydroxylation in mammals Robert Hardt, Volkmar Gieselmann, Matthias Eckhardt Institut für Biochemie und Molekularbiologie (IBMB), Uniklinikum Bonn, Nussallee 11, 53119 Bonn, Germany. Sphingolipids represent a highly diverse group of essential eukaryotic membrane lipids. They vary mainly in their type of headgroup, sphingoid base or acyl chain (i.e. length, saturation status, hydroxylation). In our group we focus on the role of sphingolipids containing N-linked α-hydroxylated fatty acids (hFA). In mammals there has been described only one enzyme until now, fatty acid 2-hydroxylase (FA2H), responsible for fatty acid α-hydroxylation. FA2H is expressed in various tissues mainly brain, spinal cord, skin, testis, ovary, kidney, stomach and intestine corresponding with significant amounts of hFA-sphingolipids. Contrasting their high incidence and diverse distribution, their functional roles in the organism are still largely unknown. One aspect of interest is the possible influence of α-hydroxylation on transport, metabolic processing and membrane distribution of sphingolipids within the cell. For example there are experimental observations indicating that GlcCer and hFA-GlcCer differ substantially in these aspects. For this reason sphingolipid α-hydroxylation may represent a key mechanism for generating membranes of differential composition. This in turn will affect a membrane’s physical properties and probably the distribution of membrane and membrane-associated proteins. Therefore using two previously described lipid transport assays (Halter et al. 2007) the possible differences in GlcCer and hFA-GlcCer transport are examined in detail. In addition studies on FA2H knock-out mice, created in our group, showed that some hFA-sphingolipids are still present in certain tissues (esp. skin), implying the existence of at least one additional fatty acid 2-hydroxylase. To discover the second enzyme a complementation assay utilizing a mouse skin cDNA library and FA2H-deficient S. cerevesiae strains is established. References: Halter et al. 2007. Pre- and post-Golgi translocation of glucosylceramide in glycosphingolipid synthesis. Journal of Cell Biology 107:101-115
57 EURON and THEME joint meeting 2011 Identification of HDAC9 on chromosome 7p21.1 as a new candidate gene for androgenetic alopecia Stefanie Heilmann 1,2* , Felix F. Brockschmidt 1,2* , Justine A. Ellis 3,4 , Sibylle Eigelshoven 5 , Sandra Hanneken 5 , Christine Herold 6 , Susanne Moebus 7 , Margrieta A. Alblas 1,2 , Bärbel Lippke 1,2 , Nadine Kluck 1,2 , Lutz Priebe 1,2 , Franziska A. Degenhardt 1,2 , Rami Abou Jamra 8 , Christian Meesters 6,9 , Karl-Heinz Jöckel 7 , Raimund Erbel 10 , Stephen Harrap 3 , Johannes Schumacher 2 , Holger Fröhlich 11 , Roland Kruse 12 , Axel M. Hillmer 13 , Tim Becker 6,9 , Markus M. Nöthen 1,2 *these authors contributed equally to this work Institute of Human Genetics, Biomedical Center, University of Bonn, Germany. Androgenetic alopecia (AGA) is the most common form of hair loss in humans affecting up to 80% of European males by the age of 80 years. Candidate gene analyses and genome-wide association studies (GWAS) have identified two major genetic risk loci: the X-chromosomal androgen receptor (AR)/ectodysplasin A2 receptor (EDA2R) locus and the paired box 1 (PAX1)/forkhead box A2 (FOXA2) locus on chromosome 20. Although these loci explain a significant fraction of the overall genetic risk for AGA, additional genetic risk factors still await identification. Here, we performed a GWAS using an case-control sample of 581 severely affected AGA cases and 617 controls, 270 of whom were men aged >60 years with no signs of AGA, representing the 20% least affecteds in the population. The best association signal was obtained for rs756853, located intronically in the histone deacetylase 9 (HDAC9) gene on chromosome 7p21.1. Fine mapping analysis within the case-control sample and a corresponding familybased analysis revealed rs756853 and rs2249817, respectively as the most highly associated variants. The association finding for rs2249817, located 6kb distally of rs756853, was confirmed within an independent Australian sample (P=0.026). A combined analysis of severely affected German and Australian cases (N=639) and unaffected controls (N=384) for rs2249817 revealed a strong association signal of P=9.09x10 -8 , odds ratio 1.63 [1.36-1.95]. Tissue expression studies demonstrated HDAC9 expression in AGA related tissues like scalp and hair follicle. Genotypespecific expression as well as splice studies revealed no strong genotypic effects, although smaller effects cannot be excluded. Pathway analyses however support the hypothesis that HDAC9 plays a functional role in AGA via interaction with the AR gene. The genetic data of the present study thus provide strong evidence that HDAC9 is the third AGA susceptibility gene.
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EURON and THEME joint PhD meeting U
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Page 105 and 106: List of Participants 103 EURON and
Page 107 and 108: Nuersailike Abuduwali University of
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Marianne Eisenhardt University of B
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Sabine Klein University of Bonn PhD
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Viktoriya Peeva University of Bonn
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Sylvie van der Kruijs Maastricht Un
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EURON and THEME joint PhD meeting

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