# Tead1 and Cardiac Adaptation

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $381,645

## Abstract

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 fa...

## Key facts

- **NIH application ID:** 9928778
- **Project number:** 5R01HL147946-02
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** MOUSUMI MOULIK
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $381,645
- **Award type:** 5
- **Project period:** 2019-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9928778

## Citation

> US National Institutes of Health, RePORTER application 9928778, Tead1 and Cardiac Adaptation (5R01HL147946-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9928778. Licensed CC0.

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