Numb通过调控肌节组装参与心肌肥厚发生的机制研究

Cardiac hypertrophy is one of the common pathological features of cardiovascular diseases, and a major mechanism for its development is abnormal assembly of sarcomere in cardiomyocyte. Recently, we unexpectedly found that Numb localizes to the sarcomeric Z-line, indicating that Numb may be a novel regulator of sarcomere assembly. Further studies showed that cardiac-specific ablation of Numb and Numblike in mice results in shorter sarcomeres with broader Z-line, and that Numb/Numblike knockout mice display signs of cardiac hypertrophy. These preliminary data suggest that Numb may participate in the regulation of cardiac hypertrophy by targeting sarcomere assembly. In this proposal we will accomplish the following aims to address molecular mechanisms by which Numb regulates cardiac hypertrophy: (1) Uncover the role of Numb in cardiac hypertrophy; (2) Determine the function of Numb in sarcomere assembly; (3) Elucidate the molecular mechanisms whereby Numb regulates sarcomere assembly. Our future findings will not only identify a new regulator of sarcomere assembly, but also advance our understanding of the mechanisms underlying cardiac hypertrophy, which could provide a new strategy for prevention and treatment of cardiac hypertrophy.

心肌肥厚是多种心血管疾病共有的病理特征，其发生发展的一个主要机制是心肌细胞肌节组装异常。我们前期研究发现Numb蛋白定位在肌节Z线，可能是一个全新的肌节组装调控因子。进一步研究发现在小鼠心肌细胞中敲除Numb和同源基因Numblike导致Z线变宽，肌节变短，同时小鼠心脏有肥厚倾向。这些前期研究结果提示Numb可能通过调控肌节组装从而影响心肌肥厚的发生。本项目将从以下几方面深入研究Numb调控心肌肥厚的分子机理：（1）揭示Numb在心肌肥厚发生中的作用；（2）确定Numb在肌节组装中的调控功能；（3）解析Numb调控肌节组装的分子机制。预期研究结果不仅将发现调控肌节组装的新因子，而且将加深对心肌肥厚发生发展机制的理解，为心肌肥厚的防治提供新策略。

心肌肥厚是多种心血管疾病共有的重要病理特征。肌节，作为心肌细胞的基本结构和功能单元，其组装异常可导致心肌肥厚的发生。目前有关肌节组装的机制还有许多未知，依托本项目，我们发现了一个新的肌节组装调控因子，即Numb蛋白。我们发现Numb蛋白定位在肌节Z线上，与α-actin相互结合，作用于细肌丝刺端（barded end），促进α-actin聚合组装成细肌丝。若Numb缺失，则会导致细肌丝组装缺陷，表现为肌节变短，Z线变粗。我们利用小鼠模型同时发现，心肌细胞缺失Numb导致小鼠心脏体积显著增大，右心室扩张，且心肌细胞横截面积变大。这些结果表明Numb缺失造成肌节结构异常从而导致心肌肥厚发生。本工作从肌节组装的角度，研究了Numb在心肌肥厚发生中的作用和机制，不仅发现了调控肌节组装的新因子，而且加深了对心肌肥厚发生发展机制的理解，为心肌肥厚的防治提供了新靶标。