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FRIMEDBIO-Fri prosj.st. med.,helse,biol

Hub Molecules Of Life

Alternative title: Livets nøkkelmolekyler

Awarded: NOK 12.5 mill.

This project aims to establish fundamental principles of how a small set of biomolecules (the “hub molecules of life”) enables biological activities and regulates cellular and organismal life. Life is based on a multitude of biochemical reactions that lead to the production of new cells and organisms, or that provide the building blocks and energy for all cellular activities. The orchestration and control of these metabolic reactions is ensured by complex networks of regulatory processes ranging from the adjustment of gene expression profiles to the finetuning of individual biochemical reactions. Astonishingly, there are a few small molecules that have key roles both in metabolic and regulatory networks. In metabolism, they mainly function as versatile, reusable units to transmit energy or to transfer chemical building blocks. In regulatory processes, these molecules provide or even serve themselves as small chemical modifiers of proteins, thereby modulating the functions of enzymes, structural proteins or regulatory factors. So far, the roles of these hub molecules have mainly been studied individually and in the context of either metabolic or regulatory processes. Here, we will use chemical, biochemical, genetic, bioinformatic, computational and clinical approaches to identify the main principals for their dual roles and how they cross-communicate between metabolic and regulatory processes. Moreover, we wish to establish how and why different hub molecules synergize in some processes and antagonize in others. In human cells, most hub molecules are produced from vitamins which may indicate important impacts of nutritional factors that could be influenced by the diet.

Metabolic disorders are a major burden on the European population and health care systems. Moreover, metabolic perturbations contribute substantially to other pathologies such as neurodegenerative disorders and cancer. The causes of metabolic dysregulation are manifold and lead to pathological shifts in biochemical processes, often in response to imbalanced nutrition. Likewise, changes in metabolism affect signalling mechanisms and gene regulation, aggravating the pathology. The tight interconnection between metabolism and signalling is still not well understood. HubMOL will fill this knowledge gap and open new horizons by exploring the functional duality of a set of small molecules that are involved in all cellular functions - the Hub Molecules Of Life (HubMOLs) including ATP, SAM (S-adenosylmethionine) and the vitamin-derived cofactors, NAD, FAD, and CoA. They mediate both metabolic reactions, but also signalling, for example, through posttranslational protein modifications (PTMs). The complexity of this emerging area requires interdisciplinary scientists equipped with a comprehensive set of skills and competences covering synthetic and analytical chemistry, experimental, computational and systems biology as well as clinical medicine. In a highly interactive team of international experts in these areas, HubMOL will develop new chemical and analytical tools enabling experimental studies of the complex interplay of cofactor metabolism and the dynamics of the PTMs they mediate. Predictive mathematical models will be developed to capture this interconnectivity and duality of hub molecules. These models will be iteratively improved through experimental verification cycles and eventually validated based on clinical data and samples from patients with neurodegenerative disorders undergoing NAD supplementation therapy. Thereby, HubMOL will establish fundamentally new insights into cofactor biology and lay the ground for patient-tailored vitamin supplementation concepts.

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FRIMEDBIO-Fri prosj.st. med.,helse,biol