Chemical biology tools for investigating the chemistry of cellular REDOX stress

用于研究细胞氧化还原应激化学的化学生物学工具

• 批准号: EP/S019901/1
• 负责人: Stuart Conway
• 金额: $ 679.71万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FS019901%2F1
• 关键词: Chemical; biology; tools; investigating; chemistry

Changes in the environment inside cells can be considered as alterations in cellular chemistry. The cellular environment can be thought to span a spectrum between reducing conditions (often characterised by a lack of oxygen, and the presence of chemicals that contain hydrogen) and oxidising conditions (often characterised by the presence of oxygen and reactive oxygen-containing species). The spectrum of REDucing to OXidising environment is known as REDOX chemistry. The REDOX environment in the cell results from external stimuli, and affects the function of the cell. Consequently, the REDOX environment can give rise to cellular changes that result in diseases. In this work, we propose that the reverse is also true - that the REDOX state of a cell at a given time will provide predictive information on the fate of a particular cell. Therefore, if it were possible to gain a global picture of the cellular REDOX state, this would be a revolutionary way of predicting cell fate, and hence treating disease. For this new technique to work we need a range of molecular tools that tell us about a given component of the REDOX state at any given time. The aim of our work is to develop and validate tools that detect the intracellular molecules that affect the cellular REDOX state, and provide imaging feedback on that state. By combing the feedback from several of these molecular tools we can infer information on the overall REDOX state. To achieve this aim we have assembled a team of people with the wide range of skills required to make the proposed molecular tools. Our team includes synthetic inorganic and organic chemists, people skilled in a range of imaging techniques, and biological scientists who will be able to apply the molecular tools that we will make. Only by combining the skills of everybody in our team will we be able to achieve the aims of this ambitious, but potentially revolutionary, programme of research.

细胞内环境的变化可以被认为是细胞化学的改变。细胞环境可以被认为跨越还原条件（通常以缺氧和存在含氢化学物质为特征）和氧化条件（通常以存在氧和活性含氧物质为特征）之间的范围。还原到氧化环境的光谱被称为氧化还原化学。细胞内的氧化还原环境由外部刺激引起，并影响细胞的功能。因此，REDOX环境可以引起导致疾病的细胞变化。在这项工作中，我们提出反过来也是正确的-细胞在给定时间的REDOX状态将提供特定细胞命运的预测信息。因此，如果有可能获得细胞氧化还原状态的全局图像，这将是预测细胞命运的革命性方法，从而治疗疾病。为了使这项新技术发挥作用，我们需要一系列分子工具，这些工具可以告诉我们在任何给定时间的REDOX状态的给定成分。我们工作的目的是开发和验证检测影响细胞REDOX状态的细胞内分子的工具，并提供该状态的成像反馈。通过梳理这些分子工具的反馈，我们可以推断出整体氧化还原状态的信息。为了实现这一目标，我们组建了一个团队，他们拥有制造所提出的分子工具所需的广泛技能。我们的团队包括合成无机和有机化学家，精通一系列成像技术的人，以及能够应用我们将制造的分子工具的生物科学家。只有结合我们团队中每个人的技能，我们才能实现这个雄心勃勃但可能具有革命性的研究计划的目标。

项目成果

Oxali(IV)Fluors: Fluorescence Responsive Oxaliplatin(IV) Complexes Identify a Hypoxia-Dependent Reduction in Cancer Cells.

• DOI: 10.1021/jacs.3c03320
• 发表时间: 2023-06-21
• 期刊: JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
• 影响因子: 15
• 作者: Boulet, Marie H. C.;Bolland, Hannah R.;Hammond, Ester M.;Sedgwick, Adam C.
• 通讯作者: Sedgwick, Adam C.

The Design, Synthesis, and Evaluation of Hypoxia-Activated Prodrugs of the KDAC Inhibitor Panobinostat

KDAC 抑制剂帕比司他缺氧激活前药的设计、合成和评价

• DOI: 10.26434/chemrxiv.13502706.v1
• 发表时间: 2020
• 作者: Calder E

Measuring ROS and redox markers in plant cells.

• DOI: 10.1039/d1cb00071c
• 发表时间: 2021-10-07
• 期刊: RSC chemical biology
• 影响因子: 4.1
• 作者: Akter S;Khan MS;Smith EN;Flashman E
• 通讯作者: Flashman E

Links between the unfolded protein response and the DNA damage response in hypoxia: a systematic review.

• DOI: 10.1042/bst20200861
• 发表时间: 2021-06-30
• 期刊: Biochemical Society transactions
• 影响因子: 3.9
• 作者: Bolland H;Ma TS;Ramlee S;Ramadan K;Hammond EM
• 通讯作者: Hammond EM

Pharmacological Inhibition of ATR Can Block Autophagy through an ATR-Independent Mechanism.

ATR的药理抑制可以通过非ATR独立的机制阻止自噬。

• DOI: 10.1016/j.isci.2020.101668
• 发表时间: 2020-11-20
• 期刊: iScience
• 影响因子: 5.8
• 作者: Bowler E;Skwarska A;Wilson JD;Ramachandran S;Bolland H;Easton A;Ostheimer C;Hwang MS;Leszczynska KB;Conway SJ;Hammond EM
• 通讯作者: Hammond EM