# Cell type-Specific Therapeutic Targeting of canonical WNT Pathway in Arrhythmogenic Cardiomyopathy

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · 2021 · $493,640

## Abstract

Arrhythmogenic cardiomyopathy (ACM) is a myocardial genetic disease whose cardinal manifestations
are ventricular arrhythmias, sudden death, myocardial fibro-adiposis, cell death, and heart failure. ACM is caused
primarily by mutations in genes encoding desmosome proteins, including desmoplakin (DSP). In the heart,
desmosomes are mainly present in myocytes and are responsible for myocardial mechanical integrity. They are
also hubs for mechanosensing and transduction, including the Hippo and canonical WNT (cWNT) pathways,
which are involved in ACM. Desmosome proteins are also expressed in the epicardium, the site of initial
manifestations of ACM phenotype. Specific role(s) of the epicardial cells in the pathogenesis of ACM is unknown.
 The cWNT pathway has emerged as an attractive therapeutic target in ACM. Experimental data,
however, are conflicting, with a spectrum ranging from suppression to activation of the cWNT in ACM. The
ambiguity along with potential fortuitous effects of systemic targeting of this major regulatory pathway have raised
considerable trepidations, leading to an impasse on therapeutic targeting of the cWNT pathway in ACM.
 We provide data in human and mouse hearts with ACM suggesting that the ambiguity is in part due to
determining the cWNT activity in cellularly heterogeneous myocardium. Accordingly, whereas the cWNT is
activated in cardiac myocytes, the whole myocardium is exposed to increased levels of secreted cWNT inhibitors
(cWNT-Is). The dysregulation is remarkable in the human hearts with ACM as transcript levels of 26 cWNT-Is
are increased, including SFRP3 protein, a classic cWNT-I. To resolve the uncertainty, we will use an
uncommitted approach of activating or suppressing the cWNT pathway specifically in cardiac myocytes and
epicardial cells and determining the phenotypic effects, including effects on expression of secreted cWNT-Is.
 Inducible Cre-deleter mice will be used to delete Dsp in cardiac myocytes or epicardial cells post-natally
while concomitantly suppressing or activating the cWNT using loss- and gain-of-function b-catenin mice. Cardiac
function, arrhythmias, apoptosis, fibro-adipogenesis and gene expression, including secretome in myocytes and
epicardial cells will be characterized. Dsp+/- epicardial cells will be conditionally tagged using the dual reporter
(Rosa26mT/mG) mice and their differentiation to other cardiac cells will be analyzed by fate mapping. Tagged cells
derived from Dsp+/- epicardial cells will be isolated and analyzed by single cell RNA-Seq to determine their
transcriptional identity and identify secretome expressed by each subset of epicardial-derived cells. Likewise,
effects of activation or suppression of the cWNT pathway on differentiation of the Dsp+/- epicardial cells to other
cardiac cell types and the secretome will be determined using gain- and loss-of-function b-catenin mice.
 The findings will determine whether cell-type specific targeting of the cWNT is a beneficial thera...

## Key facts

- **NIH application ID:** 10143294
- **Project number:** 5R01HL151737-02
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
- **Principal Investigator:** Ali J Marian
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $493,640
- **Award type:** 5
- **Project period:** 2020-04-10 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10143294

## Citation

> US National Institutes of Health, RePORTER application 10143294, Cell type-Specific Therapeutic Targeting of canonical WNT Pathway in Arrhythmogenic Cardiomyopathy (5R01HL151737-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10143294. Licensed CC0.

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