The TEA domain transcription factors (TEAD1-4) act as transcriptional mediators of the organ size control Hippo kinase pathway by interacting with Hippo pathway regulated coactivators Yes Associated Protein (YAP) and its paralogue WW Domain-containing transcription regulator protein (TAZ) and are known to regulate cellular proliferation, survival, oncogenesis and stem cell maintenance and differentiation. We recently reported a critical non-redundant role for TEAD1 in cardiomyocyte homeostasis and excitation-contraction coupling in the adult heart. Our data reveal that TEAD1 directly binds to promoter and enhancer regions of a network of genes involved in cardiac hypertrophic signaling and that multiple genes involved in cardiac hypertrophy are dysregulated upon cardiomyocyte specific deletion of Tead1. Mammalian cardiac muscle has minimal regenerative capacity and adapts to hemodynamic stress and injury primarily through cardiomyocyte hypertrophy and transcriptional reprograming. This hypertrophic remodeling is eventually maladaptive and a critical intermediate step for development of heart failure. At the molecular level cardiac hypertrophy is regulated by a complex network of cross talking signaling pathways and transcription factors. The Hippo pathway regulated TEAD1 transcriptional activity is critical for cardiomyocyte proliferation and homeostasis, but its role in cardiac hypertrophy and heart failure, though postulated, is less clear. Based on our preliminary data and other published supportive evidence, we hypothesize that TEAD1 plays a regulatory role in physiologic cardiomyocyte hypertrophic growth and pathologic cardiomyocyte hypertrophic remodeling. The broad goal of this proposal is to mechanistically delineate key cardiomyocyte hypertrophy signaling pathways regulated by TEAD1 in the adult heart and its significance in growth and heart failure. We will pursue the following three aims in this proposal:
Aim1 : Determine requirement of TEAD1 for cardiomyocyte hypertrophy during postnatal physiologic growth via regulation of IGF1 and mTOR pathways.
Aim2 : Determine if TEAD1 regulates pathologic cardiomyocyte hypertrophy in pressure overload induced cardiac remodeling and augments NFAT and MEF2 signaling.
Aim3 : Determine if TEAD1 regulates pathologic hypertrophy pathways and fetal gene program in human heart failure. Our proposed studies will critically address how TEAD1, the transcriptional target of the Hippo kinase pathway, regulates cardiomyocyte hypertrophy in physiologic and diseased states in the heart and translate this to pathologic cardiac hypertrophic remodeling in human heart failure. This will further advance our understanding of the postnatal cardiac specific role of the Hippo pathway which is currently an active target for cardiac regeneration and novel cancer therapeutic strategies. Our long-term goal is to identify new pathways and druggable therapeutic targets that can be safely modulated for treatment of human heart failure.
In this project we will determine the role of Tead1 in postnatal cardiac physiologic growth and pathologic hypertrophic remodeling using in vivo Tead1 loss of function and in vitro Tead1 loss and gain of function models and translate our findings to human heart failure and human-iPSC derived cardiomyocytes.
