Rediscovering hypoxia though RNA regulation

通过RNA调控重新发现缺氧

• 批准号: 2723181
• 金额: --
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2723181
• 关键词: Rediscovering; hypoxia; though; RNA; regulation

Hypoxia is a common stress condition for living cells and organisms, and is linked tomany diseases such as cancer. During hypoxia, cells compensate for the lack ofoxygen, by activating a series of adaptive responses to satisfy the metabolic,bioenergetic and redox demands. These responses are multifaceted requiring preciseregulation of gene expression and involving several cellular pathways. Transcriptionalmechanisms like unfolded protein response (UPR), mammalian target of rapamycin(mTOR) signalling, and gene regulation by hypoxia inducible factor (HIF) have beenextensively studied. However gene expression during hypoxia is also highly affectedpost-transcriptionally and RNA binding proteins (RBPs) are critical in controlling theseprocesses (e.g. mRNA stability and translation efficiency). Moreover recent data haveproposed the intriguing and novel idea that enzymes can also function as RNA bindingproteins, and that RNA binding would modulate their activity probably in an allostericfashion; however very little is known about the mechanistic details, or whether thishappens during hypoxia. The aims of this project are: Aim 1. To reveal changes in RNAbinding activity of RBPs in response to hypoxia through an unbiased proteomicsapproach with quantitative mass spectrometry analysis. (Year 2 - Note Year 1 is forrotation projects). Aim 2. To define the link between changes in RNA binding ofmetabolic enzymes and their metabolic activity through metabolomics approaches.(Year 2). Aim 3. The information on RBPs and hypoxia metabolism from aim 1 and 2will reveal which RPB candidates to focus on for mechanistic analysis, includingcanonical RBPs and enzymes that bind RNA during hypoxia. These will be exploredusing cellular, biochemical, biophysical and structural approaches to understand theprecise mechanisms of RNA regulation.( Year 3-4). For this we will employ a combinedstructural, biophysical, and cellular biology approach, in conjugation with state-of-artmulti-omics

缺氧是生物细胞和生物体的常见应激条件，并且是癌症等疾病。在缺氧期间，细胞通过激活一系列适应性反应来满足代谢，生物能和氧化还原需求来补偿缺乏氧。这些反应是多方面的，需要对基因表达进行精确管制，并涉及多种细胞途径。转录机械诸如未折叠的蛋白质反应（UPR），雷帕霉素（MTOR）信号传导的哺乳动物靶标以及通过缺氧诱导因子（HIF）调节的基因调节，已经进行了扩展研究。但是，缺氧期间的基因表达也受到高度影响的post-post-transcription，而RNA结合蛋白（RBP）对于控制theseprocesses（例如mRNA稳定性和翻译效率）至关重要。此外，最近的数据还提出了一种有趣而新颖的想法，即酶也可以充当RNA结合蛋白，并且RNA结合可能会在变构时代中调节其活性。然而，关于机械细节，或者在缺氧期间的记录很少了解。该项目的目的是：目标1。通过无偏见的蛋白质组学接触，并通过定量质谱分析来揭示RBPS对缺氧的RNABIND活性变化。 （2年级 - 注释1是伪造项目）。目的2。定义通过代谢酶的RNA结合的变化与代谢组学方法之间的联系。（第2年）。 AIM 3。有关AIM 1和2Will的RBP和缺氧代谢的信息，揭示了哪些RPB候选者专注于机械分析，包括在缺氧过程中结合RNA的Canonical RBP和酶。这些将通过细胞，生化，生物物理和结构方法来探索，以了解RNA调节的原理机制。（3-4年）。为此，我们将采用结合结构，生物物理和细胞生物学方法与Artmulti-Omics结合