ZeNCure aims to foster collaborative research and enhance scientific excellence at the Institute of Molecular Genetics and Genetic Engineering, University of Belgrade (IMGGE) in Serbia. This ambitious initiative brings together IMGGE with world-renowned research institutions in Germany (MPG), Portugal (CF) and the United Kingdom (UoS) along with an associated partner from Latvia (BGI RFL). The overarching goal is to elevate IMGGE's research profile by strengthening its capabilities in zebrafish (ZF) research, particularly in the context of non-communicable diseases (NCDs). NCDs pose a significant global health challenge, accounting for over 74% of all deaths worldwide. These diseases are influenced by a complex interplay of genetic, physiological, environmental, and behavioral factors. Recognizing the gravity of the situation, the EU has prioritized NCD research under the Cluster 1: Health of Horizon Europe. ZeNCure focuses on the critical role of in vivo models in NCD research, ranging from identifying genetic and environmental risk factors to testing innovative therapeutics. It leverages cutting-edge technologies, including next-generation sequencing (NGS) and bioinformatics, to enhance IMGGE's capabilities in this field. ZeNCure is poised to accelerate the professional development of both early-stage and senior researchers, as well as administrative staff. This holistic approach will not only enhance IMGGE's competitiveness in European research funding schemes but also create an inspiring and supportive research environment. ZeNCure represents a transformative endeavor that aims to strengthen scientific collaboration, improve research capabilities, and contribute to the global fight against NCDs. By bridging the gap between IMGGE and leading European research institutions, the project aspires to elevate IMGGE into a competitive and internationally recognized research institution in the Western Balkans, fostering regional integration and convergence with the EU.

The quality and quantity of consumed nutrients, including proteins, has a significant impact on health and lifespan across phyla. Essential amino acids (eAAs) are an extreme case, as many animals, including humans and Drosophila, cannot efficiently synthesize them, and thus relay solely on protein intake to obtain them. Thus, understanding the molecular changes mediating the organism´s response to such an imbalance is highly important. It is established, that animals respond to a single eAA deficiency behaviorally and metabolically. Evidently, the organism recognizes eAAs-imbalance and translates it into a specific foraging behavior and feeding decisions appropriate for compensating for such specific nutrient deficiency (i.e increased protein preference and feeding). How this is done however remains elusive. We hypothesize that this nutrient imbalance drives molecular changes that are "mirrored" in gene transcription in order to drive the response to eAA imbalance, in a tissue specific manner. In this project we will unravel molecular mechanisms involved in the metabolic and behavioral responses to eAAs imbalance , while focusing on protein appetite, in a comprehensive manner. To achieve this, we propose to employ a novel high-throughput RNA sequencing method to decipher tissue specific translational changes following eAAs deprivation. Using a bioinformatic approach, we will look into the processes underlying these transcriptional changes. Interestingly, preliminary data already reveals common biological pathways underlying the response to all eAA deficiencies the fly gut. We will genetic approaches to test the relevance of these pathways to protein feeding and to the physiological response to eAA deficiencies. We foresee this project to open an essential next step in nutritional- neuroscience research, with potential to further our knowledge about the link between stomach, gut and brain signals in driving nutrient homeostasis.

Functional-Magnetic Resonance Imaging (fMRI) has transformed our understanding of brain function due to its ability to noninvasively tag ‘active’ brain regions. Nevertheless, fMRI only detects neural activity indirectly, by relying on slow hemodynamic couplings whose relationships with underlying neural activity are not fully known. We have recently pioneered two unique MR approaches: Non-Uniform Oscillating-Gradient Spin-Echo (NOGSE) MRI and Relaxation Enhanced MR Spectroscopy (RE MRS). NOGSE-MRI is an exquisite microstructural probe, sensing cell sizes (l) with an unprecedented l^6 sensitivity (compared to l^2 in conventional approaches); RE MRS is a new spectral technique capable of recording metabolic signals with extraordinary fidelity at ultrahigh fields. This proposal aims to harness these novel concepts for mapping neural activity directly, without relying on hemodynamics. The specific objectives of this proposal are: (1) Mapping neural activity via sensing cell swellings upon activity: we hypothesize that NOGSE-fMRI can robustly sense subtle changes in cellular microstructure upon neural firings and hence convey neural activity directly. (2) Probing the nature of elicited activity via detection of neurotransmitter release: we posit that RE MRS is sufficiently sensitive to robustly detect changes in Glutamate and GABA signals upon activation. (3) Investigating widespread neural circuits in vivo via stroboscopic optogenetics: we propose to couple NOGSE-fMRI with optogenetics to resolve casual dynamics in global neural circuitry. Simulations for NOGSE-fMRI predict >4% signal changes upon subtle cell swellings; further, our in vivo RE MRS experiments have detected metabolites with SNR>50 in only 6 seconds. Hence, these two complementary –and importantly, hemodynamics-independent– approaches will represent a true paradigm shift: from indirect detection of neurovasculature couplings towards direct and noninvasive mapping of neural activity in vivo.

Alcohol-related hepatocellular carcinoma (ALD-HCC) is, in Europe, the leading cause of liver cancer (2nd most common cause of cancer-related death worldwide, affecting both men and women). ALD-HCC has a median 5-year survival rate of 15%. Yet, the prognosis is driven by the tumour stage, with curative options providing a 5-year survival exceeding 70% for early-stage HCC (<20% of cases). Therefore, interventions aiming to improve prevention and early detection are key. ALD-HCC results from the interplay between environmental determinants and genetic variations. A comprehensive characterisation of environmental factors (e.g. diet, lifestyle) linked to ALD-HCC is still lacking. We recently performed the 1st genome-wide association study of ALD-HCC and identified predisposing genetic variations. However, their role on alcohol-related liver carcinogenesis needs clarification and the genetic architecture of ALD-HCC remains mostly unknown. GENIAL brings together partners with unique expertise in clinical hepatology, single-cell and spatial multi-omics, artificial intelligence (AI) and communication and dissemination capacities. Our aim is to 1) portray genetic and environmental determinants promoting ALD-HCC; 2) evaluate how they interact at cellular level in human samples and preclinical models to get novel insights into liver carcinogenesis, and identify chemopreventive targets; and 3) assess how these determinants modulate the ALD-HCC risk in prospective cohorts of patients included in HCC surveillance programs. Environmental factors will be comprehensively characterised in an ongoing clinical trial designed to evaluate alternative methods for early-stage HCC detection. Finally, AI models, reaching the minimal viable product stage by the end of GENIAL, will be used to integrate genetic and non-genetic information (including digital imaging) to develop novel cost-effective strategies towards prevention and early-stage detection of ALD-HCC in at-risk individuals. This action is part of the Cancer Mission cluster of projects on ‘‘Understanding’.