# Novel Gene-Environment Regulatory Circuit in Chamber-Specific Growth of Perinatal Heart

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2021 · $390,000

## Abstract

PROJECT ABSTRACT .
 This proposal describes a 5-year NIH/R01 early stage investigator (ESI) application. The overall goal of
my laboratory is to elucidate the roles of gene-environment regulation and intercellular signaling in perinatal heart
chamber maturation and responses to stress during fetal to neonatal transition, a critical window for cardiac
growth, particularly, in the context of congenital heart defects (CHDs).
 The proposed studies are based on my previous work and preliminary data demonstrating a novel
regulatory circuit involving Wnt11 signaling and hypoxia in regulating chamber-specific growth uncovered by
genome-wide analysis of perinatal cardiac transcriptome. Using targeted silencing of Wnt11 gene expression
and systemic hypoxia induction in vivo, I have further established that Wnt11 regulates cardiomyocyte (CMC)
proliferation likely through modulating Rb1 activity during normal and hypoxic transition as well as in cyanotic
CHDs. In order to, mechanistically, determine whether Wnt11 affects chamber-specific growth, I have generated
both gain of function and loss of function mouse models. The Wnt11-cKO mouse model with Tamoxifen-induced
and cardiac-specific ablation of Wnt11 was established by utilizing a preexisting line carrying floxed Wnt11
(Wnt11Flox/Flox) and an αMHC-MerCreMer line. Using this novel mouse model, I obtained strong evidence
supporting that the Wnt11/Rb1 signaling is required for normal maturation of ventricular chambers. Importantly,
this regulatory loop is disrupted by hypoxia more robustly in right ventricle (RV) than left ventricle (LV) in neonatal
hearts and potentially leads to RV abnormalities in infants with cyanotic tetralogy of fallot (TOF). To achieve
CMC specific gain of function for Wnt11, I also generated an AAV9 vector for CMC specific Wnt11
overexpression (Wnt11-OE). These studies were supported by an AHA career development award and an
NIH/R56 (the High Priority Short-Term Project Award, or “Bridge Award’’).
 In this proposal, I plan to leverage our novel mouse models to establish the molecular mechanisms
mediating Wnt11/Rb1 control of chamber-specific CMC proliferation in response to hypoxia, and to explore the
pathological impact of this novel circuit in TOF. In AIM 1, I will determine the role of Wnt11/Rb1 signaling in
neonatal RV vs LV development and hypoxia response using Wnt11-cKO mouse model and AAV9-mediated
Wnt11-OE, in combination with hypoxia exposure. In AIM2, I will dissect the signaling cascade mediating Wnt11
function in neonatal rat ventricular myocytes (NRVMs) in vitro, and establish the biological relevance in the intact
neonatal heart in vivo. In AIM 3, I will examine the clinical relevance of the interplay between hypoxia and
Wnt11/Rb1 in TOF pathogenesis after birth by characterizing a well-defined TOF cohort at the transcriptomic
level. Accomplishing the proposed aims will establish a novel regulatory loop that may lead to chamber-specific
therapies for newborns with CHD...

## Key facts

- **NIH application ID:** 10242871
- **Project number:** 5R01HL153853-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Marlin Touma
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $390,000
- **Award type:** 5
- **Project period:** 2020-09-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10242871

## Citation

> US National Institutes of Health, RePORTER application 10242871, Novel Gene-Environment Regulatory Circuit in Chamber-Specific Growth of Perinatal Heart (5R01HL153853-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10242871. Licensed CC0.

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