# Elucidating the function of the CHD gene, RAPGEF5, in Wnt signaling

> **NIH NIH F30** · YALE UNIVERSITY · 2020 · $50,520

## Abstract

Project Summary/ Abstract
Congenital heart disease (CHD) is one of the leading causes of infant mortality and morbidity affecting 8 out of
every 1000 newborns in the US. Despite this massive health impact, the genetic causes of this disease are not
well understood. In order to better understand CHD, we, along with other labs, are analyzing the genomics of
CHD patients. In particular, we examined heterotaxy, a disorder of left-right (LR) patterning that can lead to
severe form of cardiac malformation due to failure of cardiac looping. From this genetic approach, we identified
RAPGEF5 as a novel candidate gene for heterotaxy and congenital heart disease, which encodes a guanine
nucleotide exchange factor that activates RAP GTPase(s). We then modeled this cardiovascular disease in
Xenopus by depleting Rapgef5, which recapitulated the human heterotaxy phenotype and demonstrated that
rapgef5 affects cardiac looping via regulating the nuclear entry of β-catenin in Wnt signaling. The main goal of
this proposal is to investigate the molecular mechanism by which rapgef5 controls the nuclear
localization of β-catenin. Of note, the mechanism of β-catenin nuclear translocation remains an outstanding
question in Wnt signaling, that has implications for developmental biology and cancer.
In this proposal, I have two specific aims based on the following hypothesis:
Hypothesis: Rapgef5 maintains nuclear Rap protein(s) in an active GTP bound state, which will preferentially
import β-catenin into the nucleus
Aim 1: Kinetic analysis of β-catenin nucleocytoplasmic shuttling in vitro
Aim 2: Identify a RAP GTPase that mediates the β-catenin nuclear transport system
Altogether, these experiments will improve our understanding of cardiac development and the role of rapgef5
in the pathogenesis of CHD as well as its role in Wnt signaling. In the future, this will benefit genetic testing and
counseling, as well as improve outcomes in CHD because treatments can be tailored to genotype rather than
solely on CHD phenotype. In addition, this application details the my training plan including research
mentorship, advanced coursework, training in new techniques, and the development of skills in scientific
professionalism, writing, and presentation of data. The research and training outlined in this application will
prepare me to pursue a career performing patient-driven research as an independent physician-scientist.

## Key facts

- **NIH application ID:** 9952111
- **Project number:** 5F30HL143878-02
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Woong Hwang
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $50,520
- **Award type:** 5
- **Project period:** 2019-06-01 → 2021-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9952111

## Citation

> US National Institutes of Health, RePORTER application 9952111, Elucidating the function of the CHD gene, RAPGEF5, in Wnt signaling (5F30HL143878-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9952111. Licensed CC0.

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