Understanding the role of alpha-actinin in cardiac disease: from molecules to mice

了解 α-肌动蛋白在心脏病中的作用：从分子到小鼠

• 批准号: 2734442
• 金额: --
• 依托单位: University of Birmingham
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2734442
• 关键词: Understanding; role; alpha; actinin; cardiac

In the heart and skeletal muscle, the Z-disc is a crucial structure to anchor thin filaments of the contractile units. Moreover, the Z-disc is recognised as a signalling hub, sensing and responding to changes in the environment. Within the Z-disc, the protein alpha-actinin crosslinks actin filaments. Missense variants in alpha-actinin have been reported to cause cardiac disease (Hypertrophic Cardiomyopathy). However, the underlying mechanisms of how such mutations cause disease are unknown. This project will investigate the consequences of a cardiac-disease causing alpha-actinin missense variant. It is expected that small changes in the protein structure lead to disturbances of contractility and protein turnover, ultimately compromising heart function. This interdisciplinary project will address the pathogenic mechanisms by exploiting biophysical and structural approaches, in combination with the investigations of an induced pluripotent stem cell derived cardiomyocyte model (both in 2D and 3D) and High-resolution Episcopic Microscopy in an in vivo model. Collectively, these studies will identify novel signalling functions of alpha-actinin, define how they are impaired in the presence of the disease-causing variant and will inform development of novel therapies targeting cardiomyopathies.

在心脏和骨骼肌中，Z盘是锚定收缩单位细丝的关键结构。此外，Z盘被认为是一个信号中心，可以感知和响应环境的变化。在Z盘内，α-辅肌动蛋白与肌动蛋白丝交联。据报道，α-辅肌动蛋白的错义变体可导致心脏病（肥厚性心肌病）。然而，这些突变如何导致疾病的潜在机制尚不清楚。这个项目将调查导致心脏病的α-辅肌动蛋白错义变异的后果。预计蛋白质结构的微小变化会导致收缩性和蛋白质周转的紊乱，最终损害心脏功能。该跨学科项目将通过利用生物物理和结构方法，结合诱导多能干细胞衍生的心肌细胞模型（2D和3D）和体内模型中的高分辨率Episcopic Microscopy的研究来解决致病机制。总的来说，这些研究将确定α-辅肌动蛋白的新信号传导功能，确定它们在致病变体存在下如何受损，并将为开发针对心肌病的新疗法提供信息。