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

基因组和转录组学研究强调心房颤动中钙信号通路

• 批准号: MR/T00052X/1
• 金额: $ 31.66万
• 依托单位: Queen Mary University of London
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FT00052X%2F1
• 关键词: Pathways; calcium; signalling; atrial; fibrillation

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.

心房颤动（AF）是一种常见的心脏病，影响英国的许多人。它通常会导致残疾症状，如心悸和呼吸困难，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AF有关。不幸的是，AF也与心力衰竭和死亡率增加有关。虽然相对常见，但导致AF发展的生物学过程尚未完全了解。这意味着我们对这种情况的治疗效果不佳。因此，需要改进AF的治疗方法，并且需要通过更好地理解驱动心律失常的机制来推动其发展。提高对导致AF的生物学过程的理解的一种策略是观察与没有AF的人相比，在患有AF的人中表达水平增加或减少的常见基因。这些全基因组关联研究（GWAS）突出了在驱动AF的生理学中潜在重要的基因产物。在多项研究中突出显示的一个这样的基因是DGK β。该基因导致细胞中产生一种蛋白质，该蛋白质参与被称为磷脂酶C/肌醇三磷酸（PLC/IP 3）途径的有据可查的细胞信号系统。然而，迄今为止，这种细胞信号级联在AF中的作用尚未得到广泛研究。已知激活该途径的各种化合物，如内皮素和血管紧张素，已知可促进动物AF，使该系统成为一个令人兴奋的探索途径。该项目的总体目标是证明，激活这种细胞内信号通路确实增加了对AF的易感性。其次，将研究这种通路可能增加AF可能性的机制。据推测，特定的钙电流可能被激活，我们将试图证明这一点。PKC/IP 3系统影响细胞的内部钙处理，我们将试图确定其在心脏心房肌细胞钙处理中的作用。我们将使用各种方法，包括药理学，电生理学和遗传学技术来研究该通路的功能。我们假设，当我们使用已知的药理学化合物在单个心房细胞以及心脏心房组织中激活该通路时，我们将能够比系统静止时更容易诱导心房颤动。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。我们将使用遗传技术，使我们能够操纵蛋白激酶C/IP 3系统的蛋白质组分，并在这样做证明其功能改变如何影响AF的诱导和维持的工作。通过这种方式，我们的目标是确定一种新的细胞途径，促进AF，并在这样做确定潜在的新的药物治疗靶点。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理解，并为进一步的治疗策略提供信息。人们希望，在未来，更有效的治疗，以预防或治疗房颤将是一个显着的大多数可能通过提高科学的理解，这种心律失常的启动和维持。

项目成果

Premature atrial and ventricular contractions detected on wearable-format electrocardiograms and prediction of cardiovascular events.

• DOI: 10.1093/ehjdh/ztad007
• 发表时间: 2023-03
• 期刊: EUROPEAN HEART JOURNAL - DIGITAL HEALTH
• 作者: Orini, Michele;van Duijvenboden, Stefan;Young, William J.;Ramirez, Julia;Jones, Aled R.;Tinker, Andrew;Munroe, Patricia B.;Lambiase, Pier D.
• 通讯作者: Lambiase, Pier D.

Machine Learning for ECG Diagnosis of LV Dysfunction.

机器学习用于心电图诊断左心室功能障碍。

• DOI: 10.1016/j.jcmg.2021.05.015
• 发表时间: 2021
• 期刊: JACC. Cardiovascular imaging
• 作者: Davies RH

A Method to Minimise the Impact of ECG Marker Inaccuracies on the Spatial QRS-T angle: Evaluation on 1,512 Manually Annotated ECGs.

• DOI: 10.1016/j.bspc.2020.102305
• 发表时间: 2021-03
• 期刊: Biomedical signal processing and control
• 影响因子: 5.1
• 作者: Young WJ;van Duijvenboden S;Ramírez J;Jones A;Tinker A;Munroe PB;Lambiase PD;Orini M
• 通讯作者: Orini M

Analysing electrocardiographic traits and predicting cardiac risk in UK biobank.

• DOI: 10.1177/20480040211023664
• 发表时间: 2021-01
• 期刊: JRSM cardiovascular disease
• 影响因子: 1.6
• 作者: Ramírez J;van Duijvenboden S;Young WJ;Orini M;Jones AR;Lambiase PD;Munroe PB;Tinker A
• 通讯作者: Tinker A

BS11 Novel T-type calcium current pharmacology shows promise in the study of atrial fibrillation

BS11 新型 T 型钙电流药理学在心房颤动研究中显示出前景

• DOI: 10.1136/heartjnl-2022-bcs.191
• 发表时间: 2022
• 作者: Jones A