Our long-term objective has been to delineate the molecular genetics and pathogenesis of hereditary cardiomyopathies, including arrhythmogenic right ventricular cardiomyopathy (ARVC). ARVC is characterized by fibro-adipocytes replacing cardiac myocytes, which leads to cardiac arrhythmias, sudden cardiac death and heart failure. There is no effective therapy for ARVC, except for heart transplantation. ARVC is primarily caused by mutations in genes encoding desmosome proteins. Desmosomes along with the adherens junctions (AJs) and the gap junctions constitute the intercalated discs (ICDs). While conventionally recognized as cell-cell adhesion structures, ICDs have emerged as major regulators of contact- mediated cell signaling. Accordingly, ICDs are implicated in regulating the Hippo pathway, which plays an important role in cellular differentiation and proliferation. The Preliminary data show extensive molecular remodeling of the ICDs in the human hearts with ARVC. The changes are associated with activation of the Hippo kinase cascade, which by phosphorylating YAP, the effector molecule, suppresses transcription through TEAD. Activation of the Hippo pathway is associated with suppression of the canonical Wnt signaling in the human hearts, which is implicated in the pathogenesis of ARVC. We posit that activation of the Hippo pathway plays a pathogenic role in ARVC.
In aim 1, upon further strengthening of the preliminary data, we will delineate the responsible mechanisms for activation of the Hippo pathway utilizing myocyte and mouse models. Preliminary data points to Neurofibromin 1 (NF2), aka Merlin, as an upstream Hippo kinase that is activated at the ICDs in the ARVC models. Through gain- and loss-of-function (GoF and LoF) approaches, the Hippo pathway will be inactivated in myocytes and mouse models and the rescue effects on cardiac structure and function, gene expression and fibro-adipogenesis will be determined.
In aim 2, we will delineate the pathogenic role of the canonical Wnt signaling and the mechanisms responsible for its suppression, in the context of active Hippo pathway. GoF and LoF targeting of the canonical Wnt and Hippo molecules will be used to determine the phenotypic effects on myocytes and mouse models.
In aim 3, we will identify the cellular origin of fibro-adipocytes in ARVC and determine the pathogenic role of the Hippo and Wnt pathways. The approaches are genetic fate mapping and knock in reporter tracing, the latter for a paracrine effect(s). The candidate cell types, based on the Preliminary data, are fibro-adipocyte progenitors, epicardial cells, pericytes, and myogenic lineage. The paracrine effects of mutant myocytes on the above cells plus resident pre-adipocytes will be tested. The pathogenic role of the Hippo pathway in their differentiation to fibro-adipocytes will be determined through LoF and GoF studies. The proposed studies are expected to provide insights into the molecular pathogenesis of ARVC and facilitate identification of new therapeutic targets for a deadly disease for which there is no effective treatment.

Public Health Relevance

Our objective is to delineate the molecular pathogenesis of arrhythmogenic right ventricular cardiomyopathy (ARVC), an important cause sudden cardiac death in the young and heart failure in middle age people. We plan to determine the role of the signaling pathways regulated at the cell junctions, namely the canonical Wnt signaling and the Hippo pathway, in the pathogenesis of ARVC and to identify the cell type(s) that differentiates to fibro-adipocytes. We hope that the discoveries will shed light onto the pathogenesis of ARVC and enhance the discovery of new pharmacological targets to prevent and treat this potentially deadly disease.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
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Lathrop, David A
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University of Texas Health Science Center Houston
Internal Medicine/Medicine
Schools of Medicine
United States
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Auguste, Gaelle; Gurha, Priyatansh; Lombardi, Raffaella et al. (2018) Suppression of Activated FOXO Transcription Factors in the Heart Prolongs Survival in a Mouse Model of Laminopathies. Circ Res 122:678-692
Marian, Ali J; Tan, Yanli; Li, Lili et al. (2018) Hypertrophy Regression With N-Acetylcysteine in Hypertrophic Cardiomyopathy (HALT-HCM): A Randomized, Placebo-Controlled, Double-Blind Pilot Study. Circ Res 122:1109-1118
Marian, Ali J (2017) Non-syndromic cardiac progeria in a patient with the rare pathogenic p.Asp300Asn variant in the LMNA gene. BMC Med Genet 18:116
Marian, Ali J (2017) Congenital Heart Disease: The Remarkable Journey From the ""Post-Mortem Room"" to Adult Clinics. Circ Res 120:895-897
Marian, A J (2017) To Seek the Holy Grail of Cardiac Progenitor Cells: An Opera in Four Acts. Circ Res 121:1208-1209
Li, Lili; Bainbridge, Matthew Neil; Tan, Yanli et al. (2017) A Potential Oligogenic Etiology of Hypertrophic Cardiomyopathy: A Classic Single-Gene Disorder. Circ Res 120:1084-1090
Karmouch, Jennifer; Zhou, Qiong Q; Miyake, Christina Y et al. (2017) Distinct Cellular Basis for Early Cardiac Arrhythmias, the Cardinal Manifestation of Arrhythmogenic Cardiomyopathy, and the Skin Phenotype of Cardiocutaneous Syndromes. Circ Res 121:1346-1359
Bainbridge, Matthew Neil; Li, Lili; Tan, Yanli et al. (2017) Identification of established arrhythmogenic right ventricular cardiomyopathy mutation in a patient with the contrasting phenotype of hypertrophic cardiomyopathy. BMC Med Genet 18:24
Marian, Ali J; Braunwald, Eugene (2017) Hypertrophic Cardiomyopathy: Genetics, Pathogenesis, Clinical Manifestations, Diagnosis, and Therapy. Circ Res 121:749-770
Lombardi, Raffaella; Chen, Suet Nee; Ruggiero, Alessandra et al. (2016) Cardiac Fibro-Adipocyte Progenitors Express Desmosome Proteins and Preferentially Differentiate to Adipocytes Upon Deletion of the Desmoplakin Gene. Circ Res 119:41-54

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