Remodelling of structure-function relationships underlying cardiac dysfunction in ageing: A multi-scale systems approach

背景人口老龄化带来的医疗保健挑战是21世纪的一个主要问题。心脏功能障碍已被认为是限制生活质量和增加猝死风险的一个致病因素；心脏老化与机械功能障碍有关，这限制了日常活动，并增加了心律失常的易感性，这可能立即危及生命。心脏的功能是由细胞和组织结构的相互作用决定的，从最小的（十亿分之一米）到最大的（整个心脏）；在衰老过程中观察到的这些细胞和组织结构的重塑（即适应）是导致衰老相关功能障碍和由此导致的心血管疾病的关键因素。此外，尽管老年人的处方率大大高于一般人群，但安全性和有效性测试通常是在年轻模型或健康志愿者中进行的；衰老相关的重塑可能对各种药物化合物的安全性和有效性产生重大影响，目前尚未有现有研究揭示。目的：我的项目旨在提供从亚细胞到整个器官尺度的结构重塑的系统级理解，这种结构重塑发生在衰老过程中，其潜在的心功能障碍机制，以及它如何调节药物干预的影响。研究项目i将开发一种新的计算模型框架，该框架将与最先进的实验方法相结合。这种综合的、多学科的方法将量化和表征从亚细胞到整个心脏尺度的重塑结构，并提供新的机制分析，将结构和功能数据联系起来，并最终解释出现的功能障碍。进行动物模型实验，提供详细、可控、全面的数据；这将辅以作为项目合作者独立研究的一部分收集的人类数据，以提供翻译相关性。湿室成像实验，定量年轻和老年大鼠的细胞和组织结构，将由博士后研究助理承担；这些数据将为基于图像的模拟提供信息，从而预测这些结构如何影响细胞和组织尺度上的机械和电功能。我将开发新的计算建模方法，以允许同时研究从纳米到整个心脏尺度的结构。这些方法将用于提供衰老过程中心功能障碍的系统级视角，揭示多种重塑结构的相对重要性和贡献，更重要的是，它们之间的相互作用。最后，计算模型将与先前开发的多种常见抗心律失常药物模型相结合，以评估衰老相关的重塑结构与药物干预的相互作用，以及这如何影响这些治疗方案的安全性和有效性。从我的项目中获得的见解将使我们更好地理解衰老过程中心功能障碍的机制，并揭示衰老与心血管疾病之间的联系。重要的是，这种见解将从细胞到器官和基本机制-通过揭示这种功能障碍的最相关和可修改的组成部分，这些见解将有助于确定成功管理功能障碍的最佳目标，以及确定可能指示从健康状态过渡到心血管疾病的潜在诊断生物标志物。这些知识将为未来的药理学和诊断学研究奠定基础，这将显著改善老年人心血管疾病的管理。

BACKGROUNDThe healthcare challenges of ageing populations are a major concern of the 21st century. Dysfunction of the heart has been implicated as a causative factor which both limits quality of life and increases the risk of sudden death; cardiac-ageing is associated with mechanical dysfunction, which limits daily activities, and increased vulnerability to arrhythmia, which can be immediately life-threatening. The function of the heart is determined by the interplay of cellular and tissue structures from the smallest (billionth of a metre) to the largest (whole-heart) scales; remodelling of (i.e. adaptations to) these cellular and tissue structures observed in ageing is a critical factor which underlies ageing-associated dysfunction and resulting cardiovascular disease. Moreover, whereas prescription rates in the aged are substantially higher than the general population, safety and efficacy testing is typically performed on young models or in healthy volunteers; ageing-associated remodelling may have a substantial impact on both the safety and efficacy of various pharmacological compounds not currently revealed by existing studies. AIMSMy project aims to provide systems-level understanding of the structural remodelling from the sub-cellular to whole-organ scales which occurs with ageing, the mechanisms by which it underlies cardiac dysfunction, and how this modulates the impact of pharmacological intervention. RESEARCH PROJECTI will develop a novel computational modelling framework which will be combined with state-of-the-art experimental approaches. This integrative, multi-disciplinary approach will quantify and characterise the remodelled structures from the sub-cellular to whole-heart scales, and provide novel mechanistic analysis which links structural and functional data and ultimately explains emergent dysfunction. Animal model experiments will be performed to provide detailed, controllable and comprehensive data; this will be supplemented by human data collected as part of project collaborators' independent research, in order to provide the translational relevance. Wet-lab imaging experiments, quantifying cellular and tissue structures in young and aged rats, will be undertaken by a post-doctoral research assistant; these data will inform image-based simulations which will predict how these structures affect mechanical and electrical function at the cellular and tissue scales. I will develop novel computational modelling methods to allow simultaneous study of structures from the nanometre to whole-heart scales. These methods will be applied to provide the systems-level perspective on cardiac dysfunction in ageing, revealing the relative importance and contributions of multiple remodelled structures and, importantly, their interaction. Finally, the computational models will be combined with previously developed models of multiple common anti-arrhythmic agents in order to assess the interaction of ageing-associated remodelled structures and pharmacological intervention, and how this affects both the safety and efficacy of these treatment options. IMPORTANCEThe insight gained from my project will give a much better understanding of the mechanisms of cardiac dysfunction in ageing, and reveal the link between ageing and cardiovascular disease. Importantly, this insight will be from cell-to-organ and on fundamental mechanisms - by revealing the most relevant and modifiable components of this dysfunction, these insights will help identify the optimum targets for successful management of dysfunction, as well as identify potential diagnostic biomarkers which may be indicative of the transition from healthy state to cardiovascular disease. This knowledge will underpin future research into pharmacology and diagnostics which will significantly improve the management of cardiovascular disease in the aged.