Tbx5 as a cardiac regulator of Yap activity

Tbx5 作为 Yap 活动的心脏调节剂

• 批准号: 8979894
• 负责人: Yocheved Schindler
• 金额: $ 5.24万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8979894
• 关键词: Adult; Amphibia; Candidate Disease Gene; Cardiac; Cardiac Myocytes; Cardiac development; Cause of Death; Cell Death; Cell Proliferation; ChIP-seq; Cicatrix; Co-Immunoprecipitations; Complex; Data; Development; Fishes; Gene Expression; Gene Expression Profiling; Gene-Modified; Genes; Goals; Heart; Heart failure; Injury; Knock-out; Lead; Modeling; Mus; Mutate; Myocardial Infarction; Natural regeneration; Nuclear; Oncogenic; Outcome; Pathway interactions; Play; Production; Proteins; Regenerative Medicine; Regulation; Research; Research Personnel; Role; Signal Transduction; Stream; Testing; Tissues; Tumor Suppression; Zebrafish; base; cardiac regeneration; cardiac repair; cardiogenesis; comparative; experience; heart dimension/size; improved; inhibitor/antagonist; mouse model; overexpression; prevent; programs; public health relevance; regenerative; research study; response to injury; skills; therapeutic development; therapeutic target; transcription factor; tumor

 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.

 描述(申请人提供)：Tbx5作为YAP活动的心脏调节器，心力衰竭是全球主要的死亡原因。与两栖动物和鱼类不同，成年哺乳动物的心脏在受伤后无法再生，导致心肌细胞数量减少，疤痕形成，收缩能力降低。最近，HIPPO信号被证明是损伤后心肌细胞增殖和心脏再生的抑制因子。此外，河马信号也被证明在心脏发育和限制心脏大小方面发挥着重要作用。河马信号的这些作用已经被证明是通过调节YAP在心肌细胞中的定位和YAP水平来实现的。抑制河马信号或增加核YAP水平可以促进损伤后的再生，并导致发育过程中心脏大小的增加。这表明河马信号是心脏修复的潜在治疗靶点。然而，河马途径在肿瘤抑制中也很重要。河马信号的减少和YAP的过度激活具有致癌功能，促进细胞增殖，防止细胞死亡。因此，为了在不促进广泛的致癌功能的情况下诱导心脏再生，识别YAP活性的心脏特异性调节因子是很重要的。Tbx5是一种成熟的心脏转录因子，已被证明与YAP相互作用，但在心肌细胞中的相互作用尚未被探索。根据初步数据，我假设Tbx5在心肌细胞中与YAP形成一个复合体，调节心脏发育和再生过程中的基因表达。为了测试这一点，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Tbx5和Yap在心肌细胞中的物理相互作用，并通过进行基因敲除和过表达实验来评估心肌细胞生产中的功能相互作用。此外，我将确定这种相互作用的下游目标，这些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了解，并可能为以组织特异性方式抑制河马信号的治疗方法的开发提供靶点。