Synthesis and Functions of Inositol Phosphates

磷酸肌醇的合成及功能

• 批准号: RGPIN-2015-05364
• 负责人: Castagner, Bastien
• 金额: $ 2.04万
• 依托单位: McGill University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2019
• 资助国家: 加拿大
• 起止时间: 2019-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=682834
• 关键词: Synthesis; Functions; Inositol; Phosphates

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.

我的研究计划旨在开发化学生物学工具来研究肌醇磷酸，一个重要的内源性分子家族。肌醇磷酸在细胞中起着许多关键作用，从细胞信号传导和钙动员到转录调节。此外，一些肌醇磷酸也被锚定在脂质双层中，在那里它们募集大量具有重要生物学后果的蛋白质。尽管肌醇磷酸在细胞中起着重要的作用，但仍然缺乏全面的了解。这部分是由于以下事实：根据磷酸化的程度和位置，存在超过60种可能的肌醇磷酸变化。此外，肌醇磷酸与数量惊人的蛋白质相互作用。获得明确定义的肌醇磷酸分子及其类似物对于在分子水平上破译其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结合对其功能具有显著影响。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用于为无机表面提供新的生物相容性涂层剂，在功能材料中具有潜在的应用。在这个研究项目中，我的目标是开发新的合成方法来制备天然肌醇磷酸酯及其非天然类似物。这些方法将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，需要开发磷酸肌醇的递送系统，以便将磷酸肌醇带到细胞胞质溶胶中。第二个总的目标是利用肌醇磷酸盐的阳离子结合特性来开发用于无机材料如生物医学应用中使用的磷酸钙的更好的涂层剂。此外，还将制备用于功能材料的各种防污、抗菌涂料。此外，肌醇磷酸盐与骨矿物羟基磷灰石的结合将被用来设计更好的骨结合剂。基于此，将开发能够检测骨组织中特定酶活性的下一代成像剂，以研究体内骨形成和溶解等重要骨过程。肌醇磷酸在生物学中的重要性保证了这里提出的化学工具的发展。这些分子将提供必要的基础知识，但也为骨组织提供新的功能材料和成像探针，并对骨疾病的新诊断模式产生影响。