The interactions between filamin C and small heat-shock proteins in cardiac mechanosignalling

细丝蛋白 C 和小热休克蛋白在心脏机械信号传导中的相互作用

• 批准号: MR/V009540/1
• 负责人: Katja Gehmlich
• 金额: $ 114.47万
• 依托单位: University of Birmingham
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FV009540%2F1
• 关键词: interactions; between; filamin; small; heat

With every heartbeat, the heart contracts, pumping blood around the body. During each contraction, the regions of the heart experience different levels of mechanical strain, so heart cells must constantly sense and respond to this strain. They do so through a process known as mechanosignalling, where specialised proteins monitor changes in the mechanical forces acting on cells, and then convert them into chemical signals that trigger other important responses in the body. Mechanosignalling is an essential function in healthy hearts, and it may be impaired in cardiac conditions, such as heart failure, where the heart becomes less able to pump the blood needed by the body. Heart failure is a significant and growing problem. It affects millions of people globally including over 920,000 people in the UK, and costs over $100bn worldwide. Aortic stenosis, a common heart valve disorder, and some inherited heart conditions also involve problems with mechanosignalling.Understanding the details of how mechanosignalling works in the heart, and what happens when it malfunctions in heart failure and other heart conditions, is important. It can help improve how we manage these conditions and could help open up new areas to explore for possible treatments.In this project, we aim to learn the details of how one particular protein complex carries out its mechanosignalling function. We believe, based on research by ourselves and others, that this complex is important for mechanosignalling in the heart. The complex is made up of a protein called filamin C that is important for cell structure and sensing mechanical strain, along with two molecular chaperones, HSPB1 and HSPB7, - proteins that help to keep other proteins in shape - and thereby helping cells to respond to mechanical stress. We will confirm that the complex plays this role, and then explore precisely how it functions, e.g. what switches protein activity on or off. Focusing on this complex will enable us to explore the details of how it works in depth. We can then apply those principles to understanding mechanosignalling more generally. To carry out this research, we, two specialist researchers (the principal investigator, PI, at the University of Birmingham and the co-principal investigator, Co-I, at the University of Oxford) have teamed up to synergistically combine our respective strengths in molecular work (Co-I) and cellular and in vivo mouse models (PI). This work will be carried out by a team of two postdoctoral research assistants with distinct skill sets, who are embedded in one of the research groups each. Our team will be supported by a network of national and international collaborators. This interdisciplinary approach will allow us to get a complete understanding of mechanosignalling of the complex ranging from exact atomic positions of its building blocks, to molecular events switching it on and off in cells to finally its consequences on the whole heart in animal models.To study this complex, we will carry out a range of different types of experiments that will shows us how mechanosignalling works at the molecular level, in cells and in the body. To look at the details of the structure of this complex and how its components interact, we will study proteins that have been taken from cells. To look at how the proteins work in cells and what that means for heart function, we will study cardiac cells and use in vivo models. Looking at changes in filamin C occurring in inherited cardiac conditions (cardiomyopathy-associated missense variants) will give insights into defective mechanosignalling and how it triggers disease. Mechanosignalling mechanisms are fundamental to our understanding of cardiac function. This work will also identify molecular targets to be explored further as a potential treatment for heart failure.

随着每一次心跳，心脏收缩，将血液泵送到全身。在每次收缩过程中，心脏的各个区域都会经历不同程度的机械应变，因此心脏细胞必须不断地感知和响应这种应变。它们通过一个被称为机械信号传导的过程来实现这一点，在这个过程中，专门的蛋白质监测作用于细胞的机械力的变化，然后将其转化为化学信号，触发体内的其他重要反应。机械信号传导是健康心脏的一项基本功能，在心脏病（如心力衰竭）中可能会受损，心脏泵送身体所需血液的能力降低。心力衰竭是一个重要且日益严重的问题。它影响了全球数百万人，包括英国超过92万人，全球成本超过1000亿美元。主动脉瓣狭窄，一种常见的心脏瓣膜疾病，以及一些遗传性心脏病也涉及机械信号的问题。了解机械信号在心脏中如何工作的细节，以及在心力衰竭和其他心脏疾病中发生故障时会发生什么，非常重要。它可以帮助改善我们如何管理这些条件，并可以帮助开辟新的领域，探索可能的治疗方法。在这个项目中，我们的目标是了解一个特定的蛋白质复合物如何执行其机械信号功能的细节。我们相信，根据我们自己和其他人的研究，这种复合物对心脏中的机械信号传导很重要。这种复合物由一种名为细丝蛋白C的蛋白质组成，细丝蛋白C对细胞结构和感知机械应力很重要，沿着两种分子伴侣，HSPB 1和HSPB 7，这两种蛋白质有助于保持其他蛋白质的形状，从而帮助细胞对机械应力做出反应。我们将确认该复合物起着这种作用，然后精确地探索它是如何发挥作用的，例如是什么打开或关闭了蛋白质的活性。专注于这个复杂的将使我们能够深入探索它如何工作的细节。然后，我们可以应用这些原则来更普遍地理解机械信号。为了开展这项研究，我们，两位专业研究人员（伯明翰大学的首席研究员PI和牛津大学的共同首席研究员Co-I）已经合作，协同联合收割机将我们各自在分子工作（Co-I）和细胞和体内小鼠模型（PI）方面的优势结合起来。这项工作将由两名博士后研究助理组成的团队进行，他们具有不同的技能，每个人都嵌入其中一个研究小组。我们的团队将得到国家和国际合作者网络的支持。这种跨学科的方法将使我们能够全面了解复合物的机械信号传导，从其结构单元的确切原子位置，到在细胞中打开和关闭它的分子事件，最终在动物模型中对整个心脏的影响。为了研究这种复合物，我们将进行一系列不同类型的实验，这些实验将向我们展示机械信号传导如何在分子水平上工作，在细胞和身体中。为了了解这种复合物的结构细节及其组分如何相互作用，我们将研究从细胞中提取的蛋白质。为了了解蛋白质在细胞中的作用以及这对心脏功能的意义，我们将研究心脏细胞并使用体内模型。研究遗传性心脏病（心肌病相关的错义变体）中细丝蛋白C的变化将深入了解缺陷性机械信号传导及其如何引发疾病。机械信号机制是我们理解心脏功能的基础。这项工作还将确定进一步探索作为心力衰竭潜在治疗方法的分子靶点。

项目成果

Functional analysis of a FLNC missense variant associated with hypertrophic cardiomyopathy

与肥厚型心肌病相关的 FLNC 错义变异的功能分析

• DOI: 10.1016/j.yjmcc.2022.08.033
• 发表时间: 2022
• 期刊: Journal of Molecular and Cellular Cardiology
• 影响因子: 5
• 作者: Azad A

Generation of a human iPSC-derived cardiomyocyte/fibroblast engineered heart tissue model.

• DOI: 10.12688/f1000research.139482.1
• 发表时间: 2023
• 期刊: F1000Research

Basic Research Approaches to Evaluate Cardiac Arrhythmia in Heart Failure and Beyond.

• DOI: 10.3389/fphys.2022.806366
• 发表时间: 2022
• 期刊: Frontiers in physiology
• 影响因子: 4
• 作者: Cumberland MJ;Riebel LL;Roy A;O'Shea C;Holmes AP;Denning C;Kirchhof P;Rodriguez B;Gehmlich K
• 通讯作者: Gehmlich K

Should young athletes be screened for cardiomyopathies to reduce the burden of sudden cardiac death in athletes?

• DOI: 10.1007/s12551-023-01085-2
• 发表时间: 2023-06
• 期刊: BIOPHYSICAL REVIEWS
• 作者: McColgan, Grace;Villarroel, Mauricio;Gehmlich, Katja
• 通讯作者: Gehmlich, Katja

How low can you go - Insight into the level of mutated protein required to cause pathogenic effects in hypertrophic cardiomyopathy

你能降到多低——深入了解导致肥厚型心肌病致病作用所需的突变蛋白水平

• DOI: 10.1016/j.jmccpl.2022.100009
• 发表时间: 2022
• 期刊: Journal of Molecular and Cellular Cardiology Plus
• 作者: Gehmlich K