# A Gata456 Pipeline of Discovery

> **NIH NIH R35** · WEILL MEDICAL COLL OF CORNELL UNIV · 2022 · $810,723

## Abstract

Three highly related genes, Gata4, Gata5, and Gata6 (referred to here as Gata456) regulate essentially every
aspect of cardiac biology, from generation of precardiac mesoderm, specification and differentiation of
endocardial, epicardial, and myocardial progenitors, heart tube formation, growth and morphogenesis,
septation and valve formation, cardioprotection and hypertrophy, and regeneration. How the three genes
regulate the spatial, temporal, and tissue-specific genetic and epigenetic networks that underlie all of these
disparate programs is poorly understood. Furthermore, mutations in each of the genes have individually been
associated with human cardiomyopathies, including atrial and ventricular septal defects, tetralogy of Fallot,
bicuspid aortic valve syndrome, and familial dilated cardiomyopathy. Other transcription factor genes, and
some terminal differentiation markers are known to be regulated by Gata456, but a major gap in understanding
is the identify of the key target genes that control intermediary functions such as lineage specification, growth,
morphogenesis, and cardio-protection. We propose a new program as a “Pipeline of Discovery” to identify
these downstream genes and probe their function in cardiogenesis and cardiac biology. The overall goal is to
define the function of each Gata456 gene throughout development and adult life in various cardiac tissues
including endocardium, myocardium, and epicardium. We seek to break the code for how the relative timing
and location of expression for each gene impacts cell fate and survival, and organ morphogenesis and
function. Complementary model systems exploit specific advantages and resolve species-specific distinctions:
the zebrafish for understanding cardiogenesis including morphogenesis, and human pluripotent stem cells for
understanding human cell identity and disease modeling. We have compiled a “toolbox” of zebrafish and hESC
lines and an expert team of investigators to facilitate a comprehensive analysis of gain-and loss-of-function
phenotypes, with a strong track record for such analyses and discovery of novel downstream targets. A
breakthrough is needed to understand how Gata456 controls all the various aspects of cardiogenesis. We are
finally in a position to define this code, by a systematic manipulation of each factor in different developmental
and tissue contexts, leading to discovery of specific key downstream target genes that carry out these diverse
functions. This project will not directly develop therapeutics for cardiac disease, but it will likely enhance
development of cellular therapies. Chiefly, it will break ground beyond current descriptions of regulatory
networks in two areas: 1) Defining the impact for loss or gain of individual Gata456 alleles at specific
developmental stages and in specific tissues to precisely define functions in developing animals (zebrafish)
and human cells (derived from human pluripotent cells). 2) Identifying the key downstream Gata456 ...

## Key facts

- **NIH application ID:** 10329974
- **Project number:** 5R35HL135778-06
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Todd R Evans
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $810,723
- **Award type:** 5
- **Project period:** 2017-01-10 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10329974

## Citation

> US National Institutes of Health, RePORTER application 10329974, A Gata456 Pipeline of Discovery (5R35HL135778-06). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10329974. Licensed CC0.

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