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Z-disc Titin in Sarcomere Assembly and Mechanotransduction

Z 盘肌联蛋白在肌节组装和机械传导中的作用

基本信息

批准号：
175225274
负责人：
Professor Dr. Michael Gotthardt
金额：
--
依托单位：
Forschungsgruppe Neuromuskuläre und kardiovaskuläre Zellbiologie
依托单位国家：
德国
项目类别：
Research Units
财政年份：
2010
资助国家：
德国
起止时间：
2009-12-31 至 2019-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/175225274?language=en
关键词：
disc Titin Sarcomere Assembly Mechanotransduction

项目摘要

The myofilament is a highly ordered periodic structure. It is based on a continuous titin filament that results from giant titin molecules overlapping end-to-end at Z-disc and M-band of the sarcomere. Assembly and disassembly of the sarcomere are important in both the physiological adaptation of muscle growth and in disease. Various models of sarcomerogenesis have been proposed that differ with respect to early thin and thick filament assembly, but ultimately agree on the necessity of adaptor proteins to cross-link Z-bodies and M-band proteins into periodic A- and I-bands. Titin is first detected in the nascent myofibril where its N-terminus attaches to the Z-bodies via alpha-actinin and less avidly vinculin. So far only little is known about the kinetics of titin’s integration into the Z-disc and how titin regulates the maturation of the sarcomere. In the proposed work we aim at elucidating titin’s role in sarcomerogenesis, visualizing the sequential integration of titin into the Z-disk and M-band. We will investigate the interrelation of biomechanics and sarcomere assembly focussing on titin based signals that govern sarcomere assembly (P1, P2, P9), Z-disc maturation (P7), serial vs. lateral growth of the sarcomere (P7), and the Z-disk based mechanosensor (P8, P9).

肌丝是高度有序的周期性结构。它基于连续的肌动蛋白丝，该肌动蛋白丝是由巨大的肌动蛋白分子在肌节的 Z 盘和 M 带处首尾重叠而产生的。肌节的组装和分解对于肌肉生长的生理适应和疾病都很重要。已经提出了各种肌瘤发生模型，这些模型在早期细丝和粗丝组装方面有所不同，但最终一致认为衔接蛋白将 Z 体和 M 带蛋白交联成周期性 A 和 I 带的必要性。肌联蛋白首先在新生肌原纤维中检测到，其 N 末端通过 α-辅肌动蛋白和不太活跃的纽蛋白连接到 Z 体。到目前为止，人们对肌动蛋白整合到 Z 盘的动力学以及肌动蛋白如何调节肌节的成熟知之甚少。在拟议的工作中，我们旨在阐明肌动蛋白在肌瘤生成中的作用，可视化肌动蛋白顺序整合到 Z 盘和 M 带中。我们将研究生物力学和肌节组装的相互关系，重点关注控制肌节组装的基于肌动蛋白的信号（P1、P2、P9）、Z 盘成熟（P7）、肌节的连续与横向生长（P7）以及基于 Z 盘的机械传感器（P8、P9）。