Pathways of calcium signalling in atrial fibrillation highlighted by genomic and transcriptomic studies

房颤(AF)是一种常见的心脏疾病，在英国影响到许多人。它通常会导致心悸和呼吸困难等致残症状，并与中风风险增加五倍有关。一些估计表明，高达30%的中风与房颤有关。不幸的是，房颤也与心力衰竭和死亡率增加有关。虽然相对常见，但导致房颤发生的生物学过程尚不完全清楚。这意味着我们对这种情况有次优的治疗方法。因此，需要改进房颤的治疗方法，并通过更好地了解导致心律失常的机制来推动房颤的发展。为了更好地理解导致房颤的生物学过程，一种策略是观察与非房颤患者相比，在房颤患者中表达水平增加或降低的常见基因。这些全基因组关联研究(GWAS)强调了在驱动房颤的生理学中潜在重要的基因产物。在多项研究中强调的一个这样的基因是DGK beta。该基因导致细胞中产生一种蛋白质，该蛋白质参与了一个众所周知的被称为磷脂酶C/三磷酸肌醇(PLC/IP3)途径的细胞信号系统。然而，到目前为止，这种细胞信号级联在房颤中的作用还没有得到广泛的研究。已知的激活这一途径的各种化合物，如内皮素和血管紧张素，都能促进动物的房颤，使这一系统成为一个令人兴奋的探索途径。这个项目的总体目标是证明激活这个细胞内信号通路确实会增加房颤的易感性。其次，这一途径可能增加房颤的可能性的机制将被研究。假设特定的钙电流可能被激活，我们将试图证明这一点。PKC/IP3系统影响细胞的内部钙处理，我们将试图确定它在心脏心房肌细胞钙处理中的作用。我们将使用多种方法来研究这一途径的功能，包括药理学、电生理和基因技术。我们假设，当我们使用已知的药理化合物激活该通路时，无论是在单个心房细胞还是在心脏心房组织中，我们将能够比系统静止时更容易诱发心房颤动。我们将使用电生理和荧光成像技术来识别心房组织中的心房颤动和单细胞中的心律失常触发事件。我们将使用基因技术来补充这项工作，这些技术允许我们操纵PKC/IP3系统的蛋白质成分，并在这样做的过程中展示其改变的功能如何影响房颤的诱导和维持。通过这种方式，我们将致力于确定一种新的促进房颤的细胞通路，并通过这样做来确定潜在的治疗新药靶点。如果我们的假设得到实验证据的支持，这项工作将增加我们对节律紊乱的机械性理解，并为进一步的治疗策略提供信息。希望在未来，通过对这种心律失常的发生和维持有更好的科学理解，能够为大多数人提供更有效的预防或治疗房颤的治疗方法。

Atrial fibrillation (AF) is a common heart condition that affects many people in the United Kingdom. It often causes disabling symptoms such as palpitations and breathlessness and is associated with a fivefold increase in stroke risk. Some estimates suggest that up to 30% of strokes are AF related. Unfortunately, AF is also associated with heart failure and increased mortality. Although relatively common, the biological processes that lead to the development of AF are incompletely understood. This means we have suboptimal treatment for the condition. Improved treatments for AF are therefore needed and their development needs to be driven by a better understanding of the mechanisms that drive the arrhythmia. One strategy to develop an improved understanding of the biological processes that lead to AF is to look at common genes that are being expressed either at an increased or decreased level in people with the condition compared to those without. These genome wide association studies (GWAS) highlight gene products that are potentially important in the physiology that drives AF. One such gene that has been highlighted in multiple studies is DGK beta. This gene causes a protein to be generated in the cell that is involved in a well-documented cell signaling system known as the phospholipase C/inositol triphosphate (PLC/IP3) pathway. However, to date the role of this cell signaling cascade in AF has not been extensively investigated. Various compounds that are known to activate this pathway, such as endothelin and angiotensin, are known to promote AF in animals making this system an exciting avenue to explore. The overall aim of this project is to demonstrate that activation of this intracellular signaling pathway does indeed increase susceptibility to AF. Secondly, mechanisms by which this pathway may increase the likelihood of AF will be investigated. It is hypothesised that particular calcium currents may be activated, and we will seek to demonstrate this. The PKC/IP3 system affects internal calcium handling by the cell and we would seek to define its role in the calcium handling of heart atrial muscle cells. We will use various methods to investigate the function of this pathway including pharmacological, electrophysiological and genetic techniques. We hypothesise that when we activate the pathway using known pharmacological compounds, in single atrial cells as well as in heart atrial tissue, we will be able to induce atrial fibrillation more easily than when the system is quiescent. We will use electrophysiological and fluorescent imaging techniques to identify atrial fibrillation in atrial tissue and arrhythmia triggering events in single cells. We will complement the work using genetic techniques that allow us to manipulate the protein components of the PKC/IP3 system and in so doing demonstrate how its altered function affects the induction and maintenance of AF. In this way, we will aim to identify a novel cellular pathway that promotes AF and in so doing identify potential new drug targets for therapy. If our hypothesis is supported by experimental evidence, the work will increase our mechanistic understanding of the rhythm disturbance and inform further therapeutic strategies. It is hoped that in the future, more effective treatments to prevent or treat AF will be available for a significant majority made possible by an improved scientific understanding of the initiation and maintenance of this arrhythmia.