Development of a platform for the assessment of cardioactive compounds by quantitative and simultaneous analysis of subcellular cAMP signalling and

开发通过定量和同步分析亚细胞 cAMP 信号传导和评估心脏活性化合物的平台

• 批准号: 2735259
• 金额: --
• 依托单位: University of Oxford
• 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-2735259
• 关键词: Development; platform; assessment; cardioactive; compounds

(title cont) cardiac myocyte electro-mechanical effects | Many elements in the heart regulate the speed and strength of heartbeats, including the messenger molecule called cyclic adenosine monophosphate (cAMP). Chemical signals, like hormones, can increase cellular cAMP that delivers the signal through phosphorylation of many targets, like ion channels, to promote or inhibit their activity. One example is when adrenaline is released during our flight-or-fight response to increase cAMP in heart cells and drive a faster heart rate. We understand that cAMP signalling operates in cardiac cells by activating targets that regulate different cellular functions depending on their subcellular localisation. Therefore, if we stimulate cAMP signalling in a specific subcellular area, the effects on the heart will be distinct to when cAMP is stimualted cell-wide. Computational modelling will be used to create an overarching model describing the signalling pathway of: 1. chemical signal, 2. spatial cAMP increase, 3. spatial target activity change, and 4. heart rate and contractility change. This will be informed through combining experiments that investigate a particular chain of events such as one experiment on signal to localised cAMP increase and another experiment on cAMP concentration to target (e.g. ion channel) activity. We can use this model to predict changes in heart rate and contractility from drugs by simulating their effects on the cAMP signalling pathwayBBSRC Priorities: Systems approaches to the biosciences; Data-driven biology; Replacement, refinement and reduction (3Rs) in research using animals

心肌细胞电-机械效应|心脏中的许多元素调节心跳的速度和强度，包括称为环磷酸腺苷（cAMP）的信使分子。化学信号，如激素，可以增加细胞cAMP，通过磷酸化许多靶点（如离子通道）来传递信号，以促进或抑制它们的活性。一个例子是，当我们在飞行或战斗反应中释放肾上腺素时，会增加心脏细胞中的cAMP并驱动更快的心率。我们理解cAMP信号传导通过激活靶点在心脏细胞中起作用，所述靶点根据其亚细胞定位调节不同的细胞功能。因此，如果我们在特定的亚细胞区域刺激cAMP信号传导，对心脏的影响将与在细胞范围内刺激cAMP时不同。计算建模将用于创建描述以下信号传导途径的总体模型：1.化学信号2空间cAMP增加，3.空间靶向活性变化，和4.心率和收缩力改变。这将通过结合研究特定事件链的实验来告知，例如一个关于局部cAMP增加的信号的实验和另一个关于cAMP浓度靶向（例如离子通道）活性的实验。我们可以使用该模型通过模拟药物对cAMP信号通路的影响来预测药物对心率和收缩力的影响BBSRC优先事项：生物科学的系统方法;数据驱动的生物学;替代、改进和减少（3R）使用动物的研究