Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz

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SHR Neuro Krebs Kardio Stoffw Microb Lipid

Doktoratskolleg "Metabolische und kardiovaskuläre Erkrankungen"

Teilprojekt zu: Doktoratskolleg "Metabolische und kardiovaskuläre Erkrankungen" (1. Förderperiode)

Abstract
Proteomic investigation of lipotoxicity in tumor-associated cachexia
Objective: To elucidate possible causes and effects of tumor-induced lipotoxicity on the proteome level.
Cachexia is commonly recognized as progressive weight loss with depletion of host reserves of adipose tissue and skeletal muscle and associated with cancers of gastrointestinal tract and lung. Survival of cancer patients is directly related to weight loss. The reduction of food intake alone is unable to explain the metabolic changes seen in cachexia. Moreover, loss of muscle and adipose tissue precedes the fall in food intake. The causes and mechanisms responsible for tumor-associated cachexia remain to be unravelled. Preliminary data generated in Gerald Hoefler´s laboratory demonstrate an involvement of adipose triglyceride lipase (ATGL) in the development of cachexia. While implantation of Lewis lung carcinoma cells into wild-type mice resulted in a vast reduction of gastrognemious muscle and white adipose tissue and a minor reduction in heart weight, none of these effects were seen in ATGL-ko mice.
Tissues from cachexia mouse models will be obtained from G. Hoefler. Proteomes from gastrognemious muscle, adipose tissues, liver, heart and spleen of wild-type and ATGL-ko mice with and without transplanted tumor will be profiled with respect to protein abundance by differential gelelectrophoresis (DIGE) and/or isotope labeling, liquid chromatography and mass spectrometry (LC-MS). Phosphoproteomics of selected cellular fractions will be performed using immobilized metal affinity chromatography (IMAC, TiO2) for phosphopeptide enrichment, isotopic labeling for quantification, LC-MS with phospho-group neutral loss scanning and database search for phospho-group modifications. Differences in lipase and esterase activities will be assessed by activity-based proteomics employing suitable probes (developed by the applicant) and by standard proteomic techniques.

Regulatory and compensatory mechanisms of lipolytic pathways
Background: While the lipolytic proteome of mouse adipose tissue has been identified (3), many of the underlying regulatory processes remain unknown. Therefore, regulatory and compensatory mechanisms of lipolytic pathways as well as changes in the overall proteome will be determined upon shut down of individual pathways (e.g. in hormone sensitive lipase (HSL)- and ATGL-deficient mice). The phenotypes of the respective mouse models differ greatly with regard to body weight, lipid accumulation, fertility and organ specific defects. Thus, large effects are expected to be observed on the protein level in adipose and other tissues as well as in macrophages and foam cells.
Objective: To elucidate the underlying regulatory, compensatory and pathogenic mechanisms of lipid accumulation on the proteome level.
Proteins interacting with recently identified lipases, as well as lipid droplet-associated proteins, which might regulate substrate accessibility, will be isolated from tissue fractions or cell lines, identified by LC-MS and analyzed for the presence of isomers and post-translational modifications, especially phosphorylation. Related tissue/cell fractions or immunoprecipitations will be profiled with respect to protein abundance by DIGE and/or isotopic labelling and LC-MS. Selected proteins will be confirmed by Western blotting. Phosphoproteomics and activity-based proteomics will be applied as described in Project 1.
Schlagworte
Medizinische Biochemie
Lokale Teilprojektleitung:
Birner-Grünberger Ruth
Laufzeit:
01.07.2010-30.06.2014
Programm:
Doktoratskolleg
Art der Forschung
Grundlagenforschung
Mitarbeiter*innen
Birner-Grünberger, Ruth, Projektleiter*in
Wallace, Pal William, Projektmitarbeiter*in
Obrist, Britta, Projektmitarbeiter*in
Fritz, Katarina, Projektmitarbeiter*in
Beteiligte MUG-Organisationseinheiten
Abteilung Zentrum für Medizinische Forschung (ZMF)
Diagnostik und Forschungsinstitut für Pathologie
Gefördert durch
FWF, Fonds zur Förderung der Wissenschaftlichen Forschung, Wien, Österreich

FWF-Grant-DOI: 10.55776/W1226
Publizierte Projektergebnisse
> Myristic acid induces proteomic and secretomic cha... J Proteomics. 2018; 181(7):118-130
> Deletion of Adipose Triglyceride Lipase Links Tria... J Proteome Res. 2018; 17(4):1415-1425
> Fatty acid-dependen effects on lipid droplet forma... Austrian Proteomics and Metabolomics Research Symposium 2018; Aug 29-31, 2018; Vienna, Austria. 2018.
> Modulation of the lipolytic phosphoproteome by iso... Austrian Proteomics and Metabolomics Reserach Symposium 2018; Aug 29-31, 2018; Vienna, Austria. 2018.
> Altered glutathione redox status in failing hearts... Austrian Proteomics and Metabolomics Research Symposium 2018; Aug 29-31, 2018; Vienna, Austria. 2018.
> The role of protein-phosphorylation in lipolysis... APRS 2017; Sep 6-8; Graz, AUSTRIA. 2017.
> Role of Adipose Triglyceride Lipase in cancer ... Moviss 2017; Oct 21-23; Vorau, Austria. 2017.
> Discovery of polyesterases using proteomics... PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Graz Medical University; 2017. pp. 266
> Mitochondrial fragmentation in fatty liver... APRS 2017; Sep 6-8; Graz, AUSTRIA. 2017.
> Adipose triglyceride lipase (ATGL) promotes oncoge... APRS 2017; Sep 6-8; Graz, AUSTRIA. 2017.
> Regulation of lipolysis revealed by activity-based... UC Berkeley Nutritional Sciences and Toxicology Departmental Seminar; Feb 24, 2017; Berkeley, USA. 2017.
> PpEst is a novel PBAT degrading polyesterase ident... Appl Microbiol Biotechnol. 2017; 101(6):2291-2303
> Role of lipolysis in cancer... HUPO 2017; Sep 17-21; Dublin, Ireland. 2017.
> Synergism of proteomics and mRNA sequencing for en... J Biotechnol. 2016; 235(2):132-138
> Tracking Protein S-Fatty Acylation with Proteomics... Chembiochem. 2016; 17(16):1488-1490
> Aberrant gene expression in human lung cancer cell... Austrian Proteomics Research Symposium; SEP 5-7, 2016; Vienna, AUSTRIA. 2016.
> Impact of trypsin artefacts in database searches... Austrian Proteomics Research Symposium; SEP 5-7, 2016; Vienna, AUSTRIA. 2016.
> A robust and simple protocol for the synthesis of ... TETRAHEDRON LETT. 2015; 56(41): 5619-5622.
> New Polyesterase from Pseudomonas oleovorans’ Secr... Austrian Proteomics Research Symposium 2015; AUG 26-28, 2015; Maria Gugging, AUSTRIA. 2015.
> Stable isotope resolved metabolomics reveal no dif... Austrian Proteomics Research Symposium 2015; AUG 26-28, 2015; Maria Gugging, AUSTRIA. 2015.
> Changes in one carbon metabolism that follow the l... Austrian Proteomics Research Symposium; AUG 26-28, 2015; Maria Gugging, AUSTRIA. 2015.
> Lipases... In: Kretsinger, RH; Uversky, VN; Permyakov, EA; editors(s). Encyclopedia of Metalloproteins. New York: Springer-Verlag; p. 1198-1206. 2013(ISBN: 978-1-4614-1533-6)
> Novel technologies applied to the study of lipolys... BHF CENTRE of RESEARCH EXCELLENCE ADIPOSE TISSUE WORKSHOP; Dec 12-13, 2013; Edinburgh, UK. 2013.
> Conformational plasticity and ligand binding of ba... J Biol Chem. 2013; 288(43):31093-31104
> Mechanism of dual specificity kinase activity of D... FEBS J. 2013; 280(18):4495-4511
> qProteomics on PLIN1 mutant lipid droplets using S... Keystone symposium ‘Adipose tissue biology’; Jan 27-Feb 1, 2013; Colorado, USA. 2013.
> Proteomic study of role of lipid metabolism induce... Proceedings of the APRS 2013. 2013; -11th Austrian Proteomic Research Symposium (APRS 2013); Sep 23-25, 2013; Innsbruck, Austria.
> Proteomic changes related to growth advantage of A... Proceedings of the APRS 2013. 2013; -11th Austrian Proteomic Research Symposium (APRS 2013); Sep 23-25, 2013; Innsbruck, Austria.
> Global protein function analysis in basic medical ... Modern Analytical Chemistry; Nov 29, 2013; Vienna, Austria. 2013.
> Glutamine-dependent regulation of beta-oxidation i... MUG Doc Day; DEC 9, 2013; Graz, AUSTRIA. 2013.
> qProteomics on PLIN1 mutant lipid droplets using S... Doctoral Day, Medical University of Graz; Dec 7, 2012; Graz, Austria. 2012.
> 10th Austrian Proteomic Research Symposium: Specia... Birner-Gruenberger, R;. editor(s). Graz: 2012. (ISBN: 978-3-200-02789-3)
> Investigating the purity of commercially available... Proceedings of the 10th Austrian Proteomic Research Symposium. 2012; -10th Austrian Proteomic Research Symposium, Special Focus on Functional Proteomics; SEP 24-26, 2012; Graz, AUSTRIA. (ISBN: 978-3-200-02789-3 )
> QProteomics on PLIN1 mutant lipid droplets using S... Proceedings of the 10th Austrian Proteomic Research Symposium. 2012; -10th Austrian Proteomic Research Symposium, Special Focus on Functional Proteomics; Sep 24-26, 2012; Graz, Austria. (ISBN: 978-3-200-02789-3 )
> Altered activity profiles of lipases in murine ATG... Proceedings of the 4th International Symposium on Lipid and Membrane biology. 2012; -4th International Symposium on Lipid and Membrane biology; Mar 8-10; Graz, Austria.
> Altered activity-based profiles of lipases in muri... Proceedings of the Keystone Symposium Cancer and Metabolism. 2012; -Keystone Symposium Cancer and Metabolism; Feb 12-17; Banff, Canada.
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