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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - mtFOIE GRAS (mitoFOIE GRAS: Non-invasive Profiling of Mitochondrial Function in Non-Alcoholic Fatty Liver Disease)

Teaser

Summary

\"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 â€˜silent killerâ€™, 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.
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Work performed

During the period covered by the report, we advance our knowledge not only in fundamental issues related to the pathophysiology of NAFLD, but also developed methodological strategies to identify novel biomarkers and interventions.
From the beginning of the project, 9 staff secondments were already finished, with several more in progress. Early-stage researchers and experienced researchers, as well as technicians were seconded from academic institutions to non-academic institutions and vice-versa. More specifically:
1 - Filomena Silva (WP1), from the CNC â€“ Center for Neuroscience and Cell Biology, University of Coimbra, Portugal explored the role of inhibitors of fatty acid oxidation in cell models of NAFLD at the company Oroboros (Austria). Filomena identified some non-specific effects of those inhibitors which can be important in the development of more specific research kits. Fatty oxidation is very relevant in mitochondria, the energy powerhouses of the cells, and which become dysfunctional during NAFLD progression.
2 - Maria Meneses (WP1) was seconded from APDP (PT) to KCL (UK). In her secondment, her aim was to understand how the diet affects hepatic mitochondrial DNA and the consequence of that to the metabolic dysfunction during NAFLD. Her results are critical to develop novel biomarkers and other diagnostic tools, and to understand dietary effects on mitochondrial function.
3 - Timea Komlodi (WP1) was seconded from Oroboros (AT) to HMGU (DE). By using isolated liver mitochondria, she investigated one of the major problems in mitochondrial biology, which is the real amount of hydrogen peroxide produced in mitochondria during normal and disease conditions. Her studies allow to increase our fundamental knowledge how liver mitochondria progress from a benign state to a dysfunctional state during NAFLD progression.
4 - Sabine Schmitt (WP1) was seconded from HMGU (DE) to Oroboros (AT) and used parallel determination of mitochondrial respiration, membrane potential, hydrogen peroxide production and energy-rich molecules to access the mechanism of mitochondrial dysfunction during NAFLD progression, developing powerful tools to elucidate the different stages of mitochondrial impairment and their involvement in disease progression.
5 - Jaschar Kabiri (WP1) was seconded from HMGU (DE) to Oroboros (AT). By using an experimental compound, the researcher investigated its effects on hepatocellular carcinoma (HCC) cells. The research opens the way to more effective treatments to HCC, the end-stage of NAFLD, and which results in significant mortality.
6 - Nina Bauer (WP2) was seconded from Mediagnost (DE) to FFUL (PT). She performed experiments with samples obtained from two different mouse models and from human patients with NAFLD, developing novel ELISA-based diagnostic kits. The different set of diagnostic parameters â€“ used separately or correlated with other markers - could facilitate staging of NAFLD and help to offer patients suitable treatment without the need of invasive methods.
7 - Theresa Thiel (WP2) was seconded from Mediagnost (DE) to CNC (PT). Her objective was to measure different proteins that may be augmented or decreased in liver samples from NAFLD models, and which may be used in the future as biomarkers. Those proteins originate in mitochondria and may be a tell-tale sign of dysfunction in that organelle.
8 - Luciana Ferreira (WP3) was seconded from CNC (PT) to Mediagnost (DE) and contributed to the development of novel diagnostic kits that would measure the same proteins validated by the previous secondee (Theresa Thiel). Her results, which need to be further optimized, will open the way to market development of these novel diagnostic kits by the company.
9 - Paula Macedo (WP4) was seconded from APDP (PT) to CNR (IT) and worked on communicating and disseminating information about the project and its activities, exploring its potential and ensuring the highest impact possible within the consortium, across Eur

Final results

Project 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.