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，影响着许多英国人。它通常会导致心悸和呼吸困难等残疾症状，并与中风风险增加五倍相关。一些估计表明，高达 30% 的中风与 AF 相关。不幸的是，房颤还与心力衰竭和死亡率增加有关。尽管相对常见，但导致房颤发生的生物过程尚不完全清楚。这意味着我们对这种情况的治疗效果不佳。因此，需要改进房颤治疗方法，并且需要通过更好地了解心律失常的驱动机制来推动其发展。加深对导致 AF 的生物过程的了解的一种策略是观察患有 AF 的人与未患 AF 的人相比表达水平升高或降低的常见基因。这些全基因组关联研究 (GWAS) 强调了在驱动 AF 的生理学中具有潜在重要作用的基因产物。多项研究中强调的此类基因之一是 DGK beta。该基因导致细胞中产生一种蛋白质，该蛋白质参与有据可查的细胞信号传导系统，称为磷脂酶 C/三磷酸肌醇 (PLC/IP3) 途径。然而，迄今为止，这种细胞信号级联在房颤中的作用尚未得到广泛研究。已知多种可激活该途径的化合物（例如内皮素和血管紧张素）可促进动物的房颤，从而使该系统成为令人兴奋的探索途径。该项目的总体目标是证明这种细胞内信号通路的激活确实会增加房颤的易感性。其次，将研究该途径可能增加房颤可能性的机制。假设特定的钙电流可能被激活，我们将设法证明这一点。 PKC/IP3 系统影响细胞的内部钙处理，我们将寻求定义其在心房肌细胞的钙处理中的作用。我们将使用各种方法来研究该途径的功能，包括药理学、电生理学和遗传技术。我们假设，当我们使用已知的药理化合物激活单个心房细胞以及心房组织中的通路时，我们将能够比系统静止时更容易诱发心房颤动。我们将使用电生理学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来补充这项工作，这些技术使我们能够操纵 PKC/IP3 系统的蛋白质成分，并以此证明其功能改变如何影响 AF 的诱导和维持。通过这种方式，我们的目标是确定一种促进 AF 的新细胞途径，并以此确定潜在的新治疗药物靶点。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制理解，并为进一步的治疗策略提供信息。希望未来通过对这种心律失常的发生和维持的科学认识的提高，可以为绝大多数人提供更有效的治疗方法来预防或治疗房颤。

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

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

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