# Role of PKP2 in epicardial structure and function

> **NIH NIH R01** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2020 · $759,436

## Abstract

PROJECT SUMMARY
Plakophilin-2 (PKP2) is a component of the desmosome. Recent studies have demonstrated that PKP2 also
acts as a scaffold for an intracellular signaling complex, and as part of the microtubule anchoring platform at
the site of cell contact. Mutations in PKP2 associate with about 50% of cases of arrhythmogenic right
ventricular cardiomyopathy (ARVC) of known genetic origin. ARVC is an inherited disease characterized by
replacement of ventricular mass with fibrous and fatty tissue, and an increased susceptibility to ventricular
arrhythmias and sudden death in the young. Our long-term goals are to: 1) establish the cellular origin of the
fibroblasts and adipocytes that populate the ventricular wall in an ARVC-affected heart, and 2) define the
molecular mechanisms that act on the progenitor cell population to bring about the disease phenotype. We
focus on epicardial cells, a cardiac-resident pluripotent stem cell population that gives rise to various non-
myocyte cardiac cells, including fibroblasts. Our central hypothesis is that, in epicardial cells in situ, PKP2
deficiency disrupts the structure of intercellular junctions and their associated intracellular signaling nodes; this
disruption alters cellular function and leads to a pro-fibrotic, pro-arrhythmogenic phenotype. Our Specific Aims
are: 1) To define the molecular anatomy of intercellular junctions, and the structure/function of the
corresponding intracellular signaling platforms in epicardial cells. Hypothesis: We postulate that in
epicardial cells, PKP2 is a functional component of: a) the intercellular junctions, b) the anchoring platform for
the microtubule plus-end, and c) the scaffolding of an intracellular signaling hub that includes beta-catenin,
PKCα, and RhoA. We further propose that in epicardial cells, loss of PKP2 expression leads to separation and
loss of components of both the intercellular junction and the signaling node, thus driving –among other events-
Rho-dependent MRTF activity, with the consequent activation of the motile gene program that facilitates the
fibrotic phenotype. 2) To characterize the consequences of PKP2 deficiency on epicardial cell function,
and their impact on cardiac anatomy and electrophysiology. Hypothesis: We propose that PKP2 deletion
in epicardial cells in vivo drives excessive mobilization of epicardium-derived progenitor cells and their
subsequent differentiation into fibro-fatty tissue both during development and in response to cardiac injury. We
further propose that expansion of the epicardium-derived fibroblast population upon injury creates
heterogeneously-distributed anatomic obstacles for propagation of the electrical impulse, and that these
obstacles differ in dimensions depending on PKP2 expression.

## Key facts

- **NIH application ID:** 9834970
- **Project number:** 5R01HL136179-04
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** Mario Delmar
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $759,436
- **Award type:** 5
- **Project period:** 2016-12-15 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9834970

## Citation

> US National Institutes of Health, RePORTER application 9834970, Role of PKP2 in epicardial structure and function (5R01HL136179-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9834970. Licensed CC0.

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