mtFOIE GRAS - Non-invasive Profiling of Mitochondrial Function in Non-Alcoholic Fatty Liver Disease
mtFOIE GRAS: H2020-MSCA-RISE-2016 - Contents and Aims
- Non-Alcoholic Fatty Liver Disease (NAFLD), including its more pathologic consequence, non-alcoholic steatohepatitis (NASH), is believed to be the most common chronic liver disease worldwide, affecting between 6 to 37% of the population. NAFLD is a so called ‘silent killer’, as clinical symptoms only surface at late stages of the disease, when it is no longer treatable: untreated, NAFLD/NASH can lead to cirrhosis and hepatocellular carcinoma, culminating in liver failure. Currently the best method of diagnosing and staging the disease is liver biopsy, a costly, invasive and somewhat risky procedure, not to mention unfit for routine assessment. Besides, no therapeutic consensus exists for NAFLD/NASH treatment.
- mtFOIE GRAS (Foie Gras being French for "fat liver") proposes to address the pressing need for non-invasive, accurate, rapid assessment of NAFLD/NASH stages, before and after intervention, through the development of biomarkers and innovative tools to follow mitochondrial (mt) dysfunction, a central mediator of fatty liver disease pathogenesis. This promising R&D strategy will also bring new knowledge about the disease mechanisms and improved understanding of the pathogenic process and disease drivers.
- To that end, mtFOIE GRAS envisages a training-through-work plan that brings together an intersectoral, multidisciplinary team of researchers and technicians experts in their fields, from basic to translational research, clinical practice, technology commercialization and public advocacy. Together with several PhD students, the team will share expertises and work synergistically along the value creation chain to address the unmet medical need of more informative NAFLD assessment. In the process, mtFOIE GRAS will endow the involved staff with excellent scientific knowledge and transferable skills while building and strengthening intersectoral cooperation among partners, thus contributing to EU RD&I excellence.
- Characterization of mitochondrial function from NAFLD tissue
- Determination of relationship between mitochondrial fat oxidation and gluconeogenic and lipogenic fluxes
- Characterization of activation and downstream function of the p66Shc-mediated signalling pathway
- Testing activation of Kupffer cells by mitochondrial protein components
- Optimization of 13C-breath tests using substrates specifically oxidized by hepatic mitochondria and microsomes
- Predict the outcome of major hepatic resection in patients with NAFLD/NASH
- Develop better blood-based assays for diagnosis and staging of NAFLD
- Explore the relationship between short chain fatty acids (SCFA) levels and mitochondrial capacity and function
- Explore specific miRNAand pro-cell death signatures for NAFLD/NASH staging and treatment
- Develop high-throughput methods to analyse circulating mitochondrial protein components
- Mitochondrial antioxidant therapy for NAFLD
- Dietary approaches for NAFLD treatment
- Physical activity for reversing NAFLD severity
- Organise networking symposia, workshops, meetings, seminar series, etc. to facilitate further mainstreaming/ upscaling beyond the project ending
- Participate in conferences, workshops, networking events etc., as appropriate
- Identify and implement exploitation strategies targeting specific groups, from policymakers to scientific and industrial levels to patient associations
- D&C actions and materials about the project findings to the general public and all relevant target audiences during the immediate project duration
- Translate the mtFOIE GRAS scientific advances into social awareness and healthier lifestyles
- Specific objectives
- The main scientific goal of mtFOIE GRAS is to identify innovative biomarkers and develop non-invasive methodologies for mitochondrial profiling in the context of NAFLD/NASH. As part of the process, novel therapeutic strategies will be envisaged. To this end, mtFOIE GRAS will create an inter-sectorial network to encourage synergies between the partners, along academic and industrial research, that shapes the project’s work-package (WP) structure outlined in Figure 2.
- Specific objectives
OROBOROS project involvement
- WP1 Prof. Amalia Gastaldelli - CNR
- WP2: Prof. Bertram Flehming - Mediagnost
- WP3: Dr. Piero Portincasa - UNIBA
- WP4: Prof. Joao Ramalho-Santos - CNC
- WP5: Dr. Paulo Oliveira - CNC
- Start: June 2017
- End: May 2021
Contribution of OROBOROS in the activities planned
- OROBOROS provides the worldwide leading concept and technology of high-resolution respirometry (HRR) applied for the functional diagnosis of mitochondrial defects, namely the MitoFit Lab with twelve Oxygraph-2k (24 O2k-Chambers) for mitochondria metabolism screen. OROBOROS will train visiting researchers in the conception and application of elaborate respiratory protocols aimed at diagnosing mitochondrial defects associated with liver diseases. Application of these protocols can be used in different preparations such as isolated liver mitochondria, liver homogenate, and permeabilized cells from liver cell lines. The latter may additionally be used to study energetics of intact liver cells. CNC and HMGU will integrate this technology in their research work while sharing their expertise in the study of NAFLD/NASH models with OROBOROS. OROBOROS will also pair with UPORTO for the highthroughput characterization of mitochondrial function isolated from animals trained in models of physical activity.
- CENTRO DE NEUROCIENCIAS E BIOLOGIACELULAR ASSOCIACAO - https://www.uc.pt/iii/linksMembros/CNC-s
mtFOIE GRAS Marie Skłodowska-Curie Participants/Beneficiaries
- CONSIGLIO NAZIONALE DELLE RICERCHE - https://www.cnr.it/
- Faculdade de Farmácia da Universidade de Lisboa - http://www.ff.ul.pt/
- HELMHOLTZ ZENTRUM MUENCHEN DEUTSCHES FORSCHUNGSZENTRUM FUER GESUNDHEIT UND UMWELT GMBH - http://www.helmholtz-muenchen.de/
- AGENCIA ESTATAL CONSEJO SUPERIOR DE INVESTIGACIONES CIENTIFICAS - www.csic.es
- UNIVERSITA DEGLI STUDI DI BARI ALDO MORO - http://www.uniba.it/
- UNIVERSIDADE DO PORTO - http://www.up.pt/
- INSTYTUT BIOLOGII DOSWIADCZALNEJ IM. M. NENCKIEGO POLSKIEJ AKADEMII NAUK - http://www.nencki.gov.pl/
- KING'S COLLEGE LONDON - http://www.kcl.ac.uk/index.aspx
- MEDIAGNOST GESELLSCHAFT FUR FORSCHUNG UND HERSTELLUNG VON DIAGNOSTIKA GMBH - http://mediagnost.de/de/startseite/
- Cetics GmbH - http://www.cetics-ht.de/
- APDP-Diabetes Portugal - www.apdp.pt
- OROBOROS INSTRUMENTS GmbH - www.oroboros.at
- Research innovation products: OROBOROS Oxygraph-2k (O2k) for high-resolution respirometry, O2kFluorometer
- 1) Gnaiger E (2014) Mitochondrial pathways and respiratory control. An introduction to OXPHOS analysis. 4th ed. Mitochondr Physiol Network 19.12. OROBOROS MiPNet Publications, Innsbruck: 80 pp. ISBN 978-3-9502399-8-0 – Open Access, see: http://www.bioblast.at/index.php/Blue_Book
- 2) Schoepf B, Schaefer G, Weber A, Talasz H, Eder IE, Klocker H, Gnaiger E (2016) Oxidative phosphorylation and mitochondrial function differ between human prostate tissue and cultured cells. FEBS J., in press.
- 3) Burtscher J, Zangrandi L, Schwarzer C, Gnaiger E (2015) Differences in mitochondrial function in homogenated samples from healthy and epileptic specific brain tissues revealed by high-resolution respirometry. Mitochondrion 25:104-12.
- 4) Krumschnabel G, Eigentler A, Fasching M, Gnaiger E (2014) Use of safranin for the assessment of mitochondrial membrane potential by high-resolution respirometry and fluorometry. Methods Enzymol 542: 163-81.
- 5) Scandurra FM, Gnaiger E (2010) Cell respiration under hypoxia: Facts and artefacts in mitochondrial oxygen kinetics. Adv Exp Med Biol 662: 7-25. For a complete list, see: http://wiki.oroboros.at/index.php/Gnaiger_E#Publications