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SHR Neuro Cancer Cardio Metab Microb Lipid

SFB LIPOTOX: Teilprojekt des Koordinationsprojekts (Pathophysiologischer Teil)

Abstract: The goal of the SFB-LIPOTOX is to elucidate the molecular and cellular
processes and pathways behind the conversion of physiological substrates,
such as FA and lipids into noxious compounds, their effects on cell and
organ function and dysfunction, and their contribution to various forms of
cell death.
The conversion of FA and lipids into lipotoxic substances occurs via two
processes: First, substrate overload, as defined by the excessive cellular
uptake of FA and lipids that exceeds the oxidative capacity of target cells.
Second, the chemical conversion and modification of FA and lipid substrates
generating biologically active signaling molecules of high toxic potential,
e.g. ceramide, lysophospholipids, lipid oxidation products, or ROS. Within
the SFB-LIPOTOX we propose to identify presently unknown lipotoxic compounds
by a mass spectrometry (MS) based lipidomic approach, to study the molecular
mechanisms of their biosynthesis and inactivation, and to elucidate the resulting biological responses in genetically modified model organisms.
We will:
*identify and characterize enzymatic processes that generate or catabolize signalling lipids;
*study the mechanisms by which FA and lipotoxic lipids affect cell signalling;
*examine lipid modification processes and their role in lipotoxicity;
*characterize the involvement of genes and their protein products in lipotoxic pathways;
*uncover lipotoxic effects on cell and organ function and lipid-induced cell death;
relate our findings in model organisms to the pathogenesis of human diseases, such as insulin resistance, atherosclerosis, and neurodegenerative disorders.

To achieve these goals, it is necessary to combine a broad spectrum of
scientific and methodological expertise from various fields in biomedicine:
lipid biology, signal transduction, cell organelle function, and apoptosis
research. Accordingly, we assembled an interdisciplinary research consortium
on the basis of scientific excellence, plus a keen interest in, and a strong
commitment to the goals of the SFB-LIPOTOX. All principal investigators have
a strong scientific track record, contribute important biological model
systems required for the project, and possess the technical expertise
required for the proposed research. The combined expertise of the consortium
members will provide a unique opportunity to investigate lipotoxic pathways
on a large scale across species, tissues, and conditions.
Within the initial funding period of the SFB-LIPOTOX (4 years) we expect to
discover unknown lipid species involved in signaling, enzymes and metabolic
processes that generate or inactivate (degrade) signalling lipids, and the
consequences of lipid signalling on cell dysfunction and death. Long term
goals beyond the initial project period include the elucidation of the
detailed physiological function of our discoveries, their contribution to
lipid and energy metabolism, and their potential application in the
diagnosis and treatment of human disease.

Local Subprojectlead:: Höfler Gerald

Duration:: 01.04.2007-31.03.2011

Programme:: Spezialforschungsbereiche (SFB)

Type of Research: basic research

Staff: Höfler, Gerald, Project Leader

MUG Research Units: Diagnostic and Research Institute of Pathology

Funded by: FWF, Fonds zur Förderung der Wissenschaftlichen Forschung, Wien, Austria

Project results published: > The role of triglyceride lipases in cancer associa... Trends Mol Med. 2013; 19(5):292-301; > A kinase-independent function of CDK6 links the ce... Cancer Cell. 2013; 24(2):167-181; > Cancer cachexia alters intracellular surfactant me... Histochem Cell Biol. 2012; 138(5):803-813; > Skeletal muscle damage and impaired regeneration d... Cell Death Dis. 2012; 3(11):e354-e354; > ATGL-mediated fat catabolism regulates cardiac mit... Nat Med. 2011; 17(9):1076-85; > Adipose triglyceride lipase plays a key role in th... J Lipid Res. 2010; 51(3): 490-9.; > Apoptosis and fibrosis are early features of heart... INT J EXP PATHOL. 2009; 90(3): 338-346.; > Synthetic LXR agonist attenuates plaque formation ... J Lipid Res. 2009; 50(2): 312-326.