Regulation of metabolism by inositol pyrophosphates

To function, our bodies need food and water. The nutrients in food are cleaved into small parts, and absorbed by the intestines. These small molecules give our bodies the building blocks to grow, develop, and make energy. This process is called metabolism, and is fine-tuned by regulatory processes. The dysregulation of metabolism is the underlining cause of diabetes and obesity, two highly debilitating human diseases often referred as 'metabolic disorders'. Metabolism is regulated at different levels, from that of the body as a whole, to the mechanisms by which individual cells control their metabolism. Deregulation of cellular metabolism is a common feature of human malignancies; cancerous cells are distinguishable from normal cells due to their altered metabolism, a characteristic used by diagnostic methods such as PET scanning. Due to the fundamental importance of metabolism, cells possess various mechanisms to fine-tune it to their physiological needs. While there has been progress in our understanding of cell metabolism, many aspects of cellular metabolic control are still unclear. Here we propose to look at this regulation from a new angle. Inositol pyrophosphates, a type of small molecule, regulate various aspects of cell activity. We propose that the many cellular features regulated by inositol pyrophosphates are underpinned by their ability to control cellular metabolism. Our idea arises from evidence suggesting that inositol pyrophosphates regulate two key parts of metabolic control: the level of the cell's energy currency, ATP; and the homeostasis of an important nutrient, phosphate, that is not only a constituent of ATP but also plays a role in the structure of DNA, our genetic material. We plan to define inositol pyrophosphates' mode operandi, dissecting how they become synthesized. More importantly, we aim to identify their ability to regulate the metabolic fluxes affecting ATP production and cellular health. Ultimately, our objective is to understand how inositol pyrophosphates are able to fine-tune cell physiology and thus affect homeostatic regulation. Dysregulation of homeostatic control could be thought of as the underlying cause of all human illness, thus our project has potentially far-reaching implications. Since scientific breakthroughs often follow methods development; we will also develop novel experimental approaches to achieve our ambitious objectives.

Cell metabolism is at the very core of any physiological process in health or disease. Understanding metabolic control is, therefore, of fundamental importance. Our work on inositol pyrophosphates (PP-IPs) has positioned this class of cellular messengers at the interface between cell metabolism and cell signalling. The evidence that PP-IPs are involved in the pathogenesis of metabolic disorders such as obesity and diabetes has increased the interest in PP-IPs as regulators of metabolism. However, despite their clear relevance, many aspects of the PP-IPs modus operandi remain poorly understood. The proposed program intends to fill these lacunae by defining several aspects of PP-IPs biology, from regulation to mechanism of action, helping to pinpoint how these molecules regulate cell metabolism. Our comprehensive program aims to define the metabolic inositol fluxes leading to PP-IPs synthesis, as well as characterising the regulation of the PP-IPs synthesizing enzymes. These studies will be accompanied by analysing how PP-IPs regulate mammalian cellular phosphate homeostasis, since the nutrient phosphate is involved in virtually every biochemical reaction, and thus understanding its homeostatic control is fundamental to comprehending metabolism. To appreciate PP-IPs signalling and metabolic control we should understand the molecular mechanisms of action. Therefore, we aim to dissect the post-translational protein modifications directly and indirectly controlled by PP-IPs. Since transformative science can only be achieved by developing novel experimental approaches, we also aim to enable visualisation of inositol phosphates by Raman spectromicroscopy, and their detection by easy-to-perform LC-MS methods. These novel techniques will help us achieve our main objective of elucidating how PP-IPs control metabolism.

The program of work by addressing, using an unconventional angle, the fundamental question: how metabolism is regulated? Will potentially have huge impact. Linking PP-IPs to metabolism control could be a game-changing prospect for scientists of different research fields interested in cellular homeostasis and its dysregulation in disease states. While our research is not directly translational, any discovery that sheds light on cellular metabolic control is potentially of translational interest. Our work could provide different ideas and approaches to ameliorating and preventing important metabolic disorders such diabetes, obesity, cancer. We will exploit these opportunity by disseminating our ideas to, and ideally to collaborate with, physicians and physiologists. The unique knowhow and expertise the program will generate will benefit the wider scientific community. The development of new analytical methods and IPs visualization by Raman spectromicroscopy will influence how researchers study this class of molecules. We will share freely these technologies affecting, as we have done in the past, on the scientific output of different researchers.
However, besides scientific knowledge our project can positively influence several aspects of UK socioeconomic development. For example, by training highly skilled peoples. The personnel involved in the project will not only receive state-of-the-art research skills but will also grow professionally utilizing the many opportunity that the LMCB and UCL are offering. Thus after their training they will be ready to contribute to UK's economic progress.
Our attempts to disseminate our scientific discovery outside the traditional scientific publication route will increase public science awareness, fundamental aspect to build a future pro-science society. The public engagement activities planned aim to share our knowledge with non-scientists to increase science's standing and explain the importance of scientific discovery in the wider society. Our project aiming to understand basic metabolism, ultimately providing an opportunity to explore and explain the underlying causes of metabolic disorders such as diabetes and obesity that are affecting a growing number of people. Thus we foresee 'engaging' public engagement activities.