Abstract

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 ?-catenin, the signal transducer of the canonical Wnt signaling and also an armadillo protein, we posit competitive interactions between PG (aka ?-catenin) and ?-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 ?-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 Description Page 6

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL088498-05
Application #
8206601
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Wang, Lan-Hsiang
Project Start
2008-01-15
Project End
2013-12-31
Budget Start
2012-01-01
Budget End
2013-12-31
Support Year
5
Fiscal Year
2012
Total Cost
$371,250
Indirect Cost
$123,750

  Institution

Name
University of Texas Health Science Center Houston
Department
Type
Schools of Medicine
DUNS #
800771594
City
Houston
State
TX
Country
United States
Zip Code
77225

  Publications

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; 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
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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