The overall objective is to delineate the molecular pathogenesis of arrhythmogenic right ventricular cardiomyopathy (ARVC) in order to prevent, attenuate and reverse its evolving phenotype. ARVC is an uncommon genetic disease caused by mutations in at least five desmosomal proteins. Patients with ARVC typically present with cardiac arrhythmias, sudden cardiac death (SCD) and in advances stages with global heart failure. SCD is the first manifestation of the disease in approximately 25% of the cases. The phenotypic hallmark of ARVC is fibro-adipocytic infiltration of the myocardium that occurs in conjunction with myocyte apoptosis. The molecular pathogenesis of ARVC and the cellular origin of fibro-adiposis are unknown. Elucidation of the genetic basis of ARVC, as a disease of mutant desmosomal proteins, has provided the opportunity to delineate the pathogenesis of its phenotype. Based on structural and functional similarities between plakoglobin (PG), a desmosomal protein and a member armadillo family, and 2-catenin, the signal transducer of the canonical Wnt signaling and also an armadillo protein, we posit competitive interactions between PG (aka 3-catenin) and 2-catenin suppresses the canonical Wnt signaling, leads to myocyte apoptosis and enhanced adipogenesis. To test the hypothesis, we generated cardiac-restricted desmoplakin (DP) deficient mice and siRNA-mediated DP-deficient atrial myocytes. We showed DP-deficiency led to nuclear translocation of PG, suppression of the canonical Wnt signaling, myocyte apoptosis, fibrosis and adipogenesis. We propose to identify the cellular origin of excess adipocytes in the heart, delineate the molecular basis of suppressed canonical Wnt signaling and prevent the phenotype by activating the canonical Wnt signaling.
The aims are: 1. To identify the cellular origin of excess adipocytes in ARVC through in vivo genetic fate-mapping and co-culture studies;2. To determine whether suppressed canonical Wnt signaling is a common mechanism for the pathogenesis of ARVC by expression of titratable levels of mutant desmosomal proteins in transgenic mice hearts;3. To delineate the mechanism by which nuclear PG suppresses the canonical Wnt signaling by studying protein-protein interactions and the effects of PG on effective assembly of Wnt core proteins complex;4. To rescue the ARVC phenotype in vivo and in vivo by activating the canonical Wnt signaling through conditional activation of degradation-resistant 2-catenin and pharmacological activation and hence, to fulfill the Koch's postulates of causality. Studies in genetically modified mice, transduced cardiac myocytes and myofibroblasts are designed to delineate the components of each aim. The results could elucidate the molecular pathogenesis of desmosomal ARVC and lead to identification of new molecular diagnostic markers and novel pharmacological targets for the treatment and prevention of ARVC in humans. Project Narrative we propose to study the molecular basis of human heart muscle disease ARVC and to prevent its development in genetically modified mouse models. ARVC is an important cause of sudden death in the young. Currently, there is no specific treatment or prevention for ARVC.
|Marian, Ali J; Braunwald, Eugene (2017) Hypertrophic Cardiomyopathy: Genetics, Pathogenesis, Clinical Manifestations, Diagnosis, and Therapy. Circ Res 121:749-770|
|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|
|Gurha, Priyatansh; Chen, Xiaofan; Lombardi, Raffaella et al. (2016) Knockdown of Plakophilin 2 Downregulates miR-184 Through CpG Hypermethylation and Suppression of the E2F1 Pathway and Leads to Enhanced Adipogenesis In Vitro. Circ Res 119:731-50|
|Marian, Ali J (2016) Clinical applications of molecular genetic discoveries. Transl Res 168:6-14|
|Marian, Ali J; van Rooij, Eva; Roberts, Robert (2016) Genetics and Genomics of Single-Gene Cardiovascular Diseases: Common Hereditary Cardiomyopathies as Prototypes of Single-Gene Disorders. J Am Coll Cardiol 68:2831-2849|
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