Plakophilin-2 (PKP2) is classically defined as a protein of the desmosome, an intercellular adhesion structure residing in the cardiac intercalated disc (ID). Mutations in PKP2 associate with most cases of gene-positive arrhythmogenic right ventricular cardiomyopathy (ARVC), a disease characterized by high propensity to life- threatening arrhythmias and myocardial structural damage, often of right ventricular predominance. Much attention has been given to the loss of cell-cell attachment at the ID as a disease mechanism. Yet, it is becoming evident that PKP2 mutations also lead to an array of poorly understood cardiomyocyte (CM)-intrinsic disturbances. Desmin intermediate filaments are anchored to the desmosome in a PKP2-dependent manner, supporting CM structural integrity and facilitating communication from the cell surface to the nucleus. Our prior work in mouse models and human patient samples found PKP2 mutation disrupts CM nuclear envelope (NE) integrity and leads to DNA damage. Based on published reports and our preliminary data, we hypothesize that PKP2 deficiency, or disease relevant PKP2 mutations, disrupt the structural, functional and molecular integrity of the cardiomyocyte nuclear envelope, leading to genomic reorganization, the DNA damage response, and altered transcription. The following aims will investigate how PKP2 deficiency disrupts the nucleus to accelerate ARVC disease progression. Aim 1: Define the impact of PKP2 deficiency on the cardiomyocyte nuclear lamina protein interactome. We hypothesize that PKP2 deficiency alters the proteome of the cardiomyocyte NE, and that this disruption is an early trigger for the disease phenotype. We will interrogate changes in the molecular ecosystem of the cardiomyocyte NE after loss of PKP2 expression using proteomics and single molecule imaging. Aim 2: Define the impact of PKP2 deficiency on cardiomyocyte genomic organization. We hypothesize that loss of NE integrity in PKP2 deficient CMs disrupts genomic organization at Lamin Associated Domains and causes transcriptional remodeling. We will determine how structural damage is transmitted from the cell membrane to the genome, focusing on changes that occur in the vicinity of the NE through advanced imaging, genomic and transcriptomic approaches. Aim 3: Investigate strategies to reduce DDR and delay cardiomyopathy in PKP2 deficient mice. We hypothesize data that PKP2 mutation induces P53-dependent DNA damage response (DDR), which may exacerbate ARVC disease progression. Genetic epistasis experiments and pharmacological approaches will investigate how the P53-dependent DDR contributes to PKP2-dependent cardiomyopathy. Defining pathological changes to nuclear architecture that precede overt myocardial structural remodeling will reveal exciting opportunities for new therapeutic strategies aimed at slowing ARVC disease progression by restoring nuclear envelope homeostasis or preventing the DNA damage response.