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

在心脏和骨骼肌中，z盘是固定收缩单元细丝的关键结构。此外，z盘被认为是一个信号中枢，感知和响应环境的变化。在z盘内，α -肌动蛋白与肌动蛋白丝交联。据报道，α -肌动蛋白的错义变异可引起心脏疾病（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α -肌动蛋白错义变异的心脏病的后果。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。这个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）和体内模型的高分辨率圣帕特里克显微镜的研究来解决致病机制。总的来说，这些研究将确定α -肌动蛋白的新信号功能，确定它们在致病变异存在下是如何受损的，并将为针对心肌病的新疗法的开发提供信息。

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.