Elucidating the role of the membrane repair protein, dysferlin, in cardiac physiology

该博士旨在确定膜修复蛋白dysferlin在衰老过程中通过维持心脏结构和功能来保持细胞内钙处理的作用。已知Dysferlin可以修复骨骼肌和心肌中受损的细胞膜，但我们实验室的数据表明，dysferlin在控制钙处理机制的结构和功能方面发挥作用。现有的数据支持dysferlin防止病理性ryanodine受体钙泄漏和保持钙稳态的概念，其中dysferlin的缺乏促进心律失常。Dysferlin的保护作用似乎是特别重要的生理应激过程中，我们认为，这种dysferlin依赖的保护作用的损失导致过早衰老。我们预测，与年龄相关的dysferlin表达的减少允许赤字在压力期间更快地积累，从而增加脆弱性。通过模拟细胞和整个心脏水平的生理应激，我们将使用尖端技术来建立dysferlin在急性和慢性机械应激期间保护心脏功能的结构和功能机制。具体而言，我们将：i）确定心脏dysferlin对衰老期间虚弱增加的贡献，ii）确定虚弱增加的潜在驱动因素，以及iii）确定虚弱增加是否预示心律失常易感性。

This PhD aims to determine the role of the membrane repair protein dysferlin in preserving intracellular calcium handling during the ageing process by maintaining cardiac structure and function. Dysferlin is known to repair damaged cell membranes in skeletal and heart muscle but data from our laboratory suggests that dysferlin plays a role in controlling the structure and function of the calcium handling machinery. Existing data supports the concept that dysferlin prevents pathological ryanodine receptor calcium leak and preserves calcium homeostasis where dysferlin's absence promotes cardiac arrhythmias. Dysferlin's protective role appears to be particularly important during physiological stress and we suggest that loss of this dysferlin-dependent protective effect contributes to premature ageing. We predict that the age associated decrease in dysferlin expression allows deficits to be accumulated more quickly during stress thereby increasing frailty. By mimicking physiological stress at the cellular and whole heart level we will use cutting edge technologies to establish the structural and functional mechanisms by which dysferlin protects cardiac function during both acute and chronic mechanical stress. Specifically we will: i) establish the contribution of cardiac dysferlin to increased frailty during ageing, ii) determine the potential drivers of increased frailty and, iii) establish if increased frailty predicts arrhythmia susceptibility.