Over 380 million people suffer from diabetes worldwide, with majority of cases being attributed to type 2 diabetes (T2D). Obesity is a major risk factor predisposing to the development of this disease. T2D is characterized by peripheral insulin resistance in combination with relative insulin deficiency that results in hyperglycemia and hyperlipidemia. Liver and adipose tissue are central for regulation of glucose and lipids levels. However, during T2D the hepatic glucose uptake is reduced while rates of gluconeogenesis and lipogenesis are increased. In the adipose tissue, T2D leads to decreased glucose uptake, perturbations in secretion of adipokines and increased lipolysis. Importantly, dysfunction of the liver and the adipose tissue during T2D is caused by defective phosphorylation signaling cascades and normalization of these pathways was shown to attenuate the course of T2D. However, the specific roles of different classes of signaling molecules in these organs remain poorly characterized. We hypothesize that the cross-talk of different classes of signaling molecules determines regulation of metabolism. Thus, we aim to identify the signaling networks regulating metabolism. The results generated in my own laboratory suggest that the Pkd family kinases are the crucial regulators of metabolic homeostasis. Specifically, Pkd1 and Pkd2 promote obesity and diabetes while Pkd3 controls liver function. Thus, we plan to characterize the molecular mechanisms controlling Pkds signaling. In parallel, we will utilize screening approaches to identify novel, non-canonical signaling modules (phosphatases and components of the ubiquitin system) regulating abundance, localization and phosphorylation of targets of Pkds and, in the long term, also other kinases implicated in T2D. By identifying and characterizing the essential signaling networks in liver and adipose tissue the project will contribute to more targeted pharmacological strategies for the treatment of T2D.

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.

Over 50 million people worldwide have epilepsy and 30% are resistant to our present therapies. Epilepsy, therefore, comprises a major burden to society and so there is a pressing need for new approaches to treatment. The brain extracellular matrix (ECM) plays a critical role in governing brain excitability and function. Although research into the role of the ECM in neuronal signalling and network function has advanced considerably in recent years, its full translational potential has yet to be realised. There is growing evidence for a major role of the ECM in epilepsy including the association between ECM protein mutations and epilepsy, changes in the ECM and associated proteins during the development of epilepsy and the strong association between the ECM and brain diseases associated with epilepsy including stroke, traumatic brain injury, neurodegeneration and autism. This proposal brings together considerable expertise from academic and industry partners in the biology of the ECM with experts in epilepsy research. This, therefore, represents a truly collaborative effort to determine not only the role of the ECM in the development of epilepsy but also novel approaches to treat and to prevent epilepsy. The academic partners will focus on specific research questions, whilst the industrial members will provide diagnostic, treatment and advanced research tools. The project has a strong translational theme and the combination of basic and translational science will be of great benefit for the training of young researchers. Trainees will be exposed to courses, workshops, joint research meetings and inter-laboratory visits. The focus of the training programme is on expanding knowledge and the application of such knowledge to address pertinent question relevant to the diagnosis, prognosis and treatment of epilepsy, so providing an ideal insight into translational neuroscience.