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

心肌细胞机电效应|心脏中的许多元素调节心跳的速度和强度，包括被称为环磷酸腺苷(CAMP)的信使分子。化学信号，如激素，可以增加细胞cAMP，通过磷酸化许多目标，如离子通道，来传递信号，以促进或抑制它们的活动。一个例子是，当我们在逃跑或战斗反应中释放肾上腺素时，心脏细胞中的cAMP增加，从而驱动更快的心率。我们了解，cAMP信号在心肌细胞中的作用是通过激活靶点来调节不同的细胞功能，这些靶点取决于它们的亚细胞定位。因此，如果我们在特定的亚细胞区域刺激cAMP信号，对心脏的影响将与cAMP在整个细胞范围内被抑制时截然不同。计算模型将被用来创建一个描述信号通路的总体模型：1.化学信号，2.空间cAMP增加，3.空间靶点活动变化，以及4.心率和收缩能力变化。这将通过结合调查特定事件链的实验来了解，例如一个关于信号到局部cAMP增加的实验和另一个关于cAMP浓度到靶点(例如离子通道)活性的实验。我们可以使用这个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能力的影响BBSRC优先事项：生物科学的系统方法；数据驱动的生物学；动物研究中的替换、改进和减少(3R)

(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