Synthesis and Functions of Inositol Phosphates

我的研究计划旨在开发化学生物学工具来研究肌醇磷酸盐，这是一种重要的内源分子家族。肌醇磷酸盐在细胞中扮演着许多重要的角色，从细胞信号和钙动员到转录调节。此外，一些肌醇磷酸盐也锚定在脂质双层，在那里它们招募了大量具有重要生物学后果的蛋白质。尽管肌醇磷酸盐在细胞中具有重要的功能，但仍缺乏全面的图景。这在一定程度上是由于这样一个事实，即根据磷酸化的程度和位置，有60多种可能的肌醇磷酸变异。此外，肌醇磷酸与数量惊人的蛋白质相互作用。获得定义明确的肌醇磷酸分子及其类似物对于在分子水平上破译它们的确切作用和机制至关重要。此外，肌醇磷酸盐与钙和其他生理阳离子的强烈结合对它们的功能有很大的影响。调节肌醇磷酸盐离子结合特性的能力将提供重要的化学工具。此外，肌醇磷酸盐的螯合性能可以为无机表面提供新的生物相容性包覆剂，在功能材料方面具有潜在的应用。*在本研究计划中，我的目标是开发新的合成方法来制备天然肌醇磷酸盐及其非天然类似物。这些方法将被用于制备创新的化学工具，以了解肌醇磷酸与蛋白质的相互作用及其在细胞中的功能。为此，开发肌醇磷酸盐的输送系统将是必要的，以便将肌醇磷酸盐带入细胞胞浆。第二个总体目标是利用肌醇磷酸盐的阳离子结合性能，为生物医学应用中使用的无机材料开发更好的包覆剂，如磷酸钙。此外，还将制备各种功能材料的防污抗菌涂料。此外，还将利用肌醇磷酸盐与骨矿羟基磷灰石的结合来设计更好的骨结合剂。在此基础上，将开发能够检测骨组织中特定酶活性的新一代显像剂，以研究体内骨形成和骨溶解等重要的骨过程。*肌醇磷酸盐在生物学中的重要性证明了本文提出的化学工具的开发。这些分子将提供基本的基础知识，也将为骨组织提供新的功能材料和成像探针，并在骨疾病的新诊断模式中发挥作用。

My research program aims at developing chemical biology tools to study inositol phosphates, an important family of endogenous molecules. Inositol phosphates play numerous crucial roles in the cell, ranging from cellular signalling and calcium mobilization to transcription regulation. Furthermore, some inositol phosphates are also anchored in the lipid bilayer where they recruit a multitude of proteins with important biological consequences. Despite the crucial functions of inositol phosphates in cell, a comprehensive picture is still lacking. This is due in part to the fact that there are over 60 possible inositol phosphate variations depending on the degree and position of phosphorylation. In addition, inositol phosphates interact with a daunting number of proteins. Access to well defined inositol phosphate molecules and their analogues is of key importance to decipher their precise role and mechanism at a molecular level. Moreover, the strong binding of inositol phosphates to calcium and other physiological cations has a dramatic impact on their functions. The ability to modulate the ion binding properties of inositol phosphates will provide important chemical tools. In addition, the chelating properties of inositol phosphates can be exploited to afford new biocompatible coating agents for inorganic surfaces, with potential applications in functional materials.***In this research program I aim to develop novel synthetic methods to prepare natural inositol phosphates and their unnatural analogues. These methods will be used to prepare innovative chemical tools to understand the interactions of inositol phosphates with proteins and their function in cells. To that effect, the development of a delivery system for inositol phosphates will be necessary in order to bring the inositol phosphates to the cell cytosol. A second general aim will be to harness the cation binding properties of inositol phosphates to develop better coating agents for inorganic material such as calcium phosphate used in biomedical applications. In addition, various anti-fouling and anti-bacterial coating for functional materials will be prepared. Furthermore, the binding of inositol phosphates to the bone mineral hydroxyapatite will be exploited to design a better bone-binding agent. Based on this, next-generation imaging agents capable of detecting specific enzymatic activity in bone tissues will be developed to study important bone processes such as bone formation and dissolution in vivo.***The importance of inositol phosphates in biology warrants the development of the chemical tools proposed here. The molecules will provide essential fundamental knowledge, but also new functional materials and imaging probes for bone tissues, with implications in novel diagnosis modalities for bone disorders.