REGULATION OF MYOCARDIAL GROWTH AND DEATH BY THE HIPPO PATHWAY

HIPPO 通路对心肌生长和死亡的调节

基本信息

批准号：
10551224
负责人：
Junichi Sadoshima
金额：
$ 58.13万
依托单位：
RUTGERS BIOMEDICAL AND HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-02-15 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10551224
关键词：
3-phosphoglycerate Acute Address Adult Affect Apoptosis Binding Blood Cardiac Cardiac Myocytes Cell Death Cessation of life ChIP-seq Chronic Phase Complex Development Down-Regulation Energy Supply Ensure Funding Genetic Transcription Glucose Glycolysis Glycolysis Induction Goals Growth Heart Heart Hypertrophy Heart failure Hypertension Hypertrophy Hypoxia Inducible Factor Intervention Investigation Knowledge Laboratories Maintenance Mediating Metabolic Metabolism Molecular Muscle Cells Myocardial Natural regeneration Nuclear Organ Size Pathogenesis Pathway interactions Phase Phosphoenolpyruvate Phosphotransferases Play Production Proteins Regulation Role SLC2A1 gene Signal Pathway Signal Transduction Signaling Molecule Sterility Stress Testing Transcriptional Coactivator with PDZ-Binding Motif Up-Regulation Vascular blood supply Warburg Effect aerobic glycolysis body system cancer cell cell growth cofactor heart cell inhibition of autophagy metabolomics mouse model novel pressure response transcription factor transcriptome tumorigenesis upstream kinase

项目摘要

Summary The Hippo signaling pathway is an evolutionarily conserved signaling pathway that controls organ size and tumorigenesis by regulating cell growth and death. We have shown that each component of the Hippo pathway is intimately involved in the pathogenesis of heart failure. YAP, the nuclear effector of the Hippo pathway, is transiently activated in response to pressure overload (PO) but downregulated during the chronic phase of PO and heart failure. Cardiac specific downregulation of YAP inhibits cardiac hypertrophy but promotes heart failure during the acute phase of PO, suggesting that endogenous YAP is salutary and mediates compensatory hypertrophy during the acute phase of PO. Although YAP is downregulated during the chronic phase of PO, forced activation of YAP at this stage is detrimental and promotes heart failure, due to de-differentiation of cardiomyocytes. Thus, YAP can be either protective or detrimental in a context-dependent manner during PO. However, it remains to be shown what makes YAP either salutary or detrimental during PO in the heart. Our preliminary results suggest that YAP promotes compensatory cardiac hypertrophy by stimulating glycolysis through upregulation of GLUT1 in the heart during the acute phase of PO, in a manner similar to aerobic glycolysis, namely the “Warburg effects” in cancer cells. Here we hypothesize that endogenous YAP mediates compensatory hypertrophy and survival of cardiomyocytes in the presence of PO through transcription of GLUT1 and consequent upregulation of glycolysis and biosynthetic molecules. YAP acts cooperatively with TEAD and HIF-1 and is involved in upregulation of GLUT1 that is activated during the acute phase of PO but inactivated during the chronic phase of PO due to differential availability of the partner transcription factors of YAP. To test these hypotheses, we will: 1. (a) Demonstrate that endogenous YAP plays an essential role in mediating upregulation of glycolysis in response to acute PO. (b) Demonstrate that activation of YAP induces accumulation of glycolytic intermediates through GLUT1- and PKM2-dependent mechanisms. (c) Demonstrate that YAP-induced upregulation of GLUT1 is essential for the maintenance of glycolysis and consequent upregulation of compensatory cardiac hypertrophy in response to acute PO. 2. Demonstrate that YAP-induced upregulation of GLUT1 is mediated through direct binding of YAP to TEAD and/or HIF-1 and resultant cooperative actions during acute PO. We will use genetically altered mouse models, cultured adult cardiomyocytes, metabolomic analyses, transcriptome analyses and ChIP sequencing analyses to address these issues. Successful completion of this project will provide novel information about the molecular switch that controls the glycolytic pathway and compensatory hypertrophy in the heart and how YAP differentially controls signaling mechanisms to mediate both salutary and detrimental effects in the heart during PO.

概括 Hippo 信号通路是一条进化上保守的信号通路，控制器官大小和我们已经证明 Hippo 途径的每个组成部分都通过调节细胞生长和死亡来促进肿瘤发生。 YAP 是 Hippo 通路的核效应子，与心力衰竭的发病机制密切相关。因压力过载 (PO) 而短暂激活，但在 PO 慢性期下调 YAP 的心脏特异性下调可抑制心脏肥大，但促进心脏功能。 PO 急性期失败，表明内源性 YAP 是有益的并介导代偿 PO 急性期肥大尽管 YAP 在 PO 慢性期下调。由于 YAP 的去分化，在此阶段强制激活 YAP 会造成痛苦并促进心力衰竭因此，YAP 在 PO 期间可以以上下文相关的方式发挥保护作用或有害作用。然而，是什么让 YAP 在 PO 期间对我们的内心有益或痛苦仍有待证明。初步结果表明，YAP 通过刺激糖酵解促进代偿性心脏肥大通过在 PO 急性期期间心脏中 GLUT1 的上调，其方式类似于有氧运动糖酵解，即癌细胞中的“Warburg 效应”，我们在此与内源性 YAP 介导进行斗争。 PO 存在下，心肌细胞的代偿性肥大和存活通过转录 GLUT1 以及随之而来的糖酵解和生物合成分子的上调与 YAP 协同作用。 TEAD 和 HIF-1 参与 GLUT1 的上调，GLUT1 在 PO 急性期被激活，但由于伙伴转录因子的可用性差异，在 PO 慢性期失活为了检验这些假设，我们将： 1. (a) 证明内源性 YAP 在介导急性 PO 中糖酵解的上调 (b) 证明 YAP 的激活会诱导。通过 GLUT1 和 PKM2 依赖性机制积累糖酵解中间体 (c) 证明。 YAP 诱导的 GLUT1 上调对于维持糖酵解和随后的糖酵解至关重要 2. 证明 YAP 诱导的代偿性心脏肥大。 GLUT1 的上调是通过 YAP 与 TEAD 和/或 HIF-1α 的直接结合介导的急性 PO 期间的合作行动我们将使用培养的成年小鼠基因模型。心肌细胞、代谢组学分析、转录组分析和 ChIP 测序分析来解决这些问题的成功完成将提供有关分子开关的新信息。控制心脏中的糖酵解途径和代偿性肥大以及 YAP 有何差异控制信号机制以介导 PO 期间心脏的有益和不健康影响。