Tbx5 as a cardiac regulator of Yap activity

 描述（由申请人提供）：Tbx 5作为雅普活动的心脏调节剂。心力衰竭是全球死亡的主要原因。与两栖动物和鱼类不同，成年哺乳动物的心脏在损伤后不能再生，导致心肌细胞数量减少，瘢痕形成和收缩力降低。最近，Hippo信号已被证明是心肌细胞增殖和损伤后心脏再生的抑制剂。此外，Hippo信号也被证明在心脏发育和限制心脏大小方面发挥重要作用。Hippo信号传导的这些作用已被证明是通过调节心肌细胞内的雅普定位和雅普水平。抑制Hippo信号传导或增加核雅普水平可以促进对损伤的响应再生，以及导致发育期间心脏尺寸的增加。这表明Hippo信号传导是心脏修复的潜在治疗靶点。然而，Hippo通路在肿瘤抑制中也很重要。Hippo信号传导的减少和雅普的过度活化具有致癌功能，促进细胞增殖并防止细胞死亡。因此，重要的是鉴定雅普活性的心脏特异性调节剂，以诱导心脏再生而不促进广泛的致癌功能。tbx 5是一种公认的心脏转录因子，已被证明与雅普相互作用，尽管在心肌细胞中的相互作用尚未被探索。基于初步数据，我假设Tbx5与心肌细胞中的雅普形成复合物，以调节心脏发育和再生过程中的基因表达。为了验证这一点，我将使用斑马鱼和小鼠模型来比较再生和非再生心脏。我将确认心肌细胞中Tbx5和雅普之间的物理相互作用，以及通过进行敲低和过表达实验来评估心肌细胞产生中的功能相互作用。此外，我将确定这种相互作用的下游目标，在再生和发展中发挥作用。这将进一步加深我们对心脏再生相关因素的理解，并可能为开发以组织特异性方式抑制Hippo信号传导的治疗药物提供靶点。

 DESCRIPTION (provided by applicant): Tbx5 as a cardiac regulator of Yap activity Heart failure is a leading cause of death worldwide. Unlike amphibians and fish the adult mammalian heart fails to regenerate after injury leading to a reduction in cardiomyocyte number, scar formation and reduced contractility. Recently, Hippo signaling has been shown to be an inhibitor of cardiomyocyte proliferation and cardiac regeneration after injury. In addition, Hippo signaling has also been shown to play an important role in cardiac development and in limiting heart size. These roles of Hippo signaling have been shown to be through regulation of Yap localization and Yap levels within cardiomyocytes. Inhibition of Hippo signaling or increased levels of nuclear Yap can promote regeneration in response to injury as well as lead to an increase in cardiac size during development. This presents Hippo signaling as a potential therapeutic target for cardiac repair. However, the Hippo pathway is also important in tumor suppression. Reductions of Hippo signaling and hyper activation of Yap have oncogenic functions, promoting cell proliferation and preventing cell death. Therefore, it is important to identify cardiac specifc regulators of Yap activity in order to induce cardiac regenerative without promoting wide spread oncogenic functions. Tbx5 a well-established cardiac transcription factor has been shown to interact with yap although an interaction in cardiomyocytes has not been explored. Based on preliminary data I hypothesize Tbx5 forms a complex with Yap in cardiomyocytes to regulate gene expression during heart development and regeneration. To test this I will employ both zebrafish and mouse models to compare the regenerative and non-regenerative heart. I will confirm a physical interaction between Tbx5 and Yap in cardiomyocytes as well as evaluate a functional interaction in cardiomyocyte production by performing knockdown and overexpression experiments. Additionally, I will identify downstream targets of this interaction that play a role in regeneration and development. This will further our understanding of factors involved in cardiac regeneration and may provide targets for development of therapeutics that repress Hippo signaling in a tissue specific manner.