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, PKC?, 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.
Arrhythmias are a major cause of morbidity and mortality, at great economic and societal cost. We focus on the mechanisms for arrhythmias that result from mutations in a protein called plakophilin-2 (PKP2), which cause a disease called ?arrhythmogenic right ventricular cardiomyopathy.? We use modern physiology and microscopy methods to observe the anatomy of molecules in the scale of 10 millionths of an inch, follow heart development, and study the arrhythmias of mouse hearts deficient in PKP2, as a way to better understand their mechanisms and potential for new therapies.
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|Sorgen, Paul L; Trease, Andrew J; Spagnol, Gaelle et al. (2018) Protein?Protein Interactions with Connexin 43: Regulation and Function. Int J Mol Sci 19:|