Understanding the molecular mechanisms that control cardiac cell cycle progression and exit is essential and required for effective cardiac regeneration therapy. The majority of mammalian cardiomyocytes undergoes terminal differentiation and rapidly switches from hyperplasia to hypertrophy resulting in binucleation soon after birth. However, a small population of differentiating but immature and mononucleated cardiomyocytes, similar to prenatal ones, may retain a proliferative ability and could enter the cell cycle to produce new cardiomyocytes. This project aims to determine the roles of canonical Wnt/ b-catenin signaling and the brahma-related gene 1 (Brg1) chromatin remodeling complex in cardiac cell cycle progression and exit during postnatal heart development and acute myocardial infarction. Our preliminary data suggest that adenomatous polyposis coli (APC), a tumor suppressor frequently mutated in colon cancer, is a potential master switch that turns off cardiomyocyte proliferation, but how APC regulates the cardiac cell cycle remains an unanswered question. The central hypothesis to test is if the decline of Wnt/b-catenin activity leads to Brg1 downregulation after birth and is directly responsible for the transition from cardia proliferation to hypertrophy. We further propose that Brg1 is sufficient and required for cardiac cell cycle progression. Using gene therapy, cardiac-specific genetic targeting and mutagenesis, we will create models for gain- and loss-of-function in Wnt signaling and the Brg1 chromatin remodeling complex. With these models, we will pursue these specific aims: 1) To determine the roles of APC and b-catenin in CMs during the postnatal hyperplasia-hypertrophy transition of CMs;2) To investigate the role of Brg1 in b- catenin signaling during postnatal heart development and after acute myocardial infarction. Our ultimate goal is to determine if manipulating b-catenin signaling and the Brg1 chromatin remodeling complex can stimulate cardiac regeneration and repair after acute and chronic myocardial damage.

Public Health Relevance

Although enhancing cardiac regeneration is being actively pursued as a novel therapeutic approach for cardiac diseases, poor understanding of cardiac cell cycle regulation has impeded the development of effective regenerative medicine in the heart. This project aims to determine the roles of canonical Wnt/ b-catenin signaling and the Brg1 chromatin remodeling complex in cardiac cell cycle progression and exit during postnatal heart development and in acute myocardial infarction. Our ultimate goal is to identify novel therapeutic targets to stimulate the growth and division of new heart muscle cells after injury to adult hearts.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL111480-03
Application #
8692588
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Schramm, Charlene A
Project Start
2012-07-18
Project End
2017-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Rochester
Department
Pathology
Type
School of Medicine & Dentistry
DUNS #
City
Rochester
State
NY
Country
United States
Zip Code
14627
Hou, Ning; Ye, Bo; Li, Xiang et al. (2016) Transcription Factor 7-like 2 Mediates Canonical Wnt/β-Catenin Signaling and c-Myc Upregulation in Heart Failure. Circ Heart Fail 9:
Ye, Bo; Hou, Ning; Xiao, Lu et al. (2016) Dynamic monitoring of oxidative DNA double-strand break and repair in cardiomyocytes. Cardiovasc Pathol 25:93-100
Wang, Ning; Huo, Rong; Cai, Benzhi et al. (2016) Activation of Wnt/β-catenin signaling by hydrogen peroxide transcriptionally inhibits NaV1.5 expression. Free Radic Biol Med 96:34-44
Cai, Yujun; Nagel, David J; Zhou, Qian et al. (2015) Role of cAMP-phosphodiesterase 1C signaling in regulating growth factor receptor stability, vascular smooth muscle cell growth, migration, and neointimal hyperplasia. Circ Res 116:1120-32
Li, Jie; Ma, Wenxia; Li, Huizhong et al. (2015) NEDD8 Ultimate Buster 1 Long (NUB1L) Protein Suppresses Atypical Neddylation and Promotes the Proteasomal Degradation of Misfolded Proteins. J Biol Chem 290:23850-62
Ye, Bo; Hou, Ning; Xiao, Lu et al. (2015) APC controls asymmetric Wnt/β-catenin signaling and cardiomyocyte proliferation gradient in the heart. J Mol Cell Cardiol 89:287-96
Lei, Daoxiong; Li, Faqian; Su, Huabo et al. (2013) Hepatic deficiency of COP9 signalosome subunit 8 induces ubiquitin-proteasome system impairment and Bim-mediated apoptosis in murine livers. PLoS One 8:e67793
Le, Nhat-Tu; Heo, Kyung-Sun; Takei, Yuichiro et al. (2013) A crucial role for p90RSK-mediated reduction of ERK5 transcriptional activity in endothelial dysfunction and atherosclerosis. Circulation 127:486-99
Ye, Bo; Ge, Yao; Perens, Gregory et al. (2013) Canonical Wnt/β-catenin signaling in epicardial fibrosis of failed pediatric heart allografts with diastolic dysfunction. Cardiovasc Pathol 22:54-7
Su, Huabo; Li, Jie; Osinska, Hanna et al. (2013) The COP9 signalosome is required for autophagy, proteasome-mediated proteolysis, and cardiomyocyte survival in adult mice. Circ Heart Fail 6:1049-57

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