Cardiac myosin light chain 1 dependent regulatory mechanisms in dilated cardiomyopathy

扩张型心肌病中心肌肌球蛋白轻链1依赖性调节机制

• 批准号: 414993933
• 负责人: Professor Dr. Benjamin Meder
• 金额: --
• 依托单位: Klinik für Kardiologie, Angiologie und Pulmologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/414993933?language=en
• 关键词: Cardiac; myosin; light; chain; dependent

The essential myosin light chain (cMLC-1) as part of the sarcomere is closely interacting with motor-myosin. As shown by the applicant, cMLC-1 can be phosphorylated at two highly conserved phosphorylation sites, Thr64 and Ser195. Lack of the phosphorylation site at Ser195 causes severely impaired cardiac contractility in a genetic zebrafish model, hinting at a pivotal role in sarcomere function. However, the contribution and precise regulation of cMLC-1 in dilated cardiomyopathy or heart failure is unknown.The proposed research aims to unravel the functional relevance of cMLC-1 posttranslational phosphorylation and the associated regulatory pathways and dissect its contribution to human heart disease. We aim to identify and validate cMLC-1 interaction partners in vitro with special focus on kinases and phosphatases responsible for its posttranslational modification. The knowledge about direct interaction partners will be used to define underlying regulatory pathways as well as modes of activation and inhibition, a preamble for potential therapeutic translation. In a next step towards therapeutic modulation, the functional consequence of altered cMLC-1 regulation is investigated in vivo. We will explore the biological significance of genetic alterations and posttranslational modifications of cMLC-1 as well as the identified interaction partners on heart function in engineered transgenic zebrafish models. Elucidating the molecular properties of cMLC-1 will help to deepen our basic understanding of sarcomere function and define targets for molecular treatment strategies of cardiomyopathy and heart failure.

肌球蛋白轻链（cMLC-1）作为肌节的一部分，与运动肌球蛋白密切相互作用。如申请人所示，cMLC-1可以在两个高度保守的磷酸化位点Thr 64和Ser 195磷酸化。在遗传斑马鱼模型中，Ser 195磷酸化位点的缺乏导致心脏收缩力严重受损，暗示了肌节功能的关键作用。然而，cMLC-1在扩张型心肌病或心力衰竭中的作用和精确调控尚不清楚，拟开展的研究旨在阐明cMLC-1翻译后磷酸化的功能相关性及其相关调控途径，并剖析其在人类心脏病中的作用。我们的目标是确定和验证cMLC-1的相互作用的合作伙伴在体外特别关注的激酶和磷酸酶负责其翻译后修饰。关于直接相互作用伙伴的知识将用于定义潜在的调控途径以及激活和抑制模式，这是潜在治疗翻译的序言。在治疗调节的下一步中，在体内研究改变的cMLC-1调节的功能后果。我们将探索cMLC-1的遗传改变和翻译后修饰的生物学意义，以及在工程化转基因斑马鱼模型中确定的心脏功能相互作用伙伴。阐明cMLC-1的分子特性将有助于加深我们对肌节功能的基本理解，并为心肌病和心力衰竭的分子治疗策略确定目标。