Cells contain tiny signalling molecules called inositol phosphates that control everything from insulin release to cell growth, but scientists cannot see where these molecules are located inside living cells. Current methods require grinding up cells and extracting the molecules for analysis—a slow, laborious process that destroys all spatial information. This means researchers know *that* these molecules exist in different amounts in different cell types, but not *where* they are active within a single cell. Without this spatial map, it is impossible to understand how the same molecule can trigger different responses in different parts of the cell. This project will develop fluorescent probes and advanced Raman microscopy techniques to make inositol phosphates visible under a microscope for the first time. The approach is inspired by similar tools that already work for related lipid molecules. If successful, this fundamental science project will give cell biologists a new way to watch signalling molecules in action. Understanding where and when these molecules accumulate could eventually reveal why insulin signalling fails in diabetes or how cancer cells hijack growth pathways—but the immediate goal is simply to build the tools to see the invisible.
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Playing multifaceted roles in the regulation of fundamental cellular processes, the water-soluble myo-inositol phosphates (InsPs) and their pyrophosphate derivatives (PP-InsPs) are ubiquitously present across eukaryotic cells. The concentration and subcellular localisation of individual InsP species, however, vary widely depending on the organism and cell type. Moreover, recent advances in biochemical analytical techniques have prompted the hypothesis of separate, kinetically distinct InsP pools with divergent signalling mechanisms. While understanding the heterogeneous cellular distributions of these crucial metabolites is essential for elucidating their diverse biological functions, their biochemical extraction and analysis remain extremely time-consuming and labour-intensive. Inspired by the success of Fluorescent Lipid-Associated Reporters (FLAREs) in visualising lipid-bound phosphatidylinositol phosphates (PtdInsPs), this project aims to develop an analogous strategy to create fluorescent biosensors and chemical probes for visualising InsPs. Building on prior studies demonstrating Raman spectroscopy’s capability to localise and analyse both inorganic polyphosphate (PolyP) and inositol hexakisphosphate (InsP₆) within biological specimens, this project further seeks to advance Raman microscopy techniques in combination with fluorescent and chemical probes. Together, these approaches aim to directly identify, localise, distinguish, and quantify cellular InsP profiles, thereby providing spatially resolved insights into InsP metabolism. Keywords: inositol phosphate; inositol pyrophosphate; phytic acid; FLARE; Raman spectromicroscopy; probe design
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