Cardiovascular diseases continue to be a leading cause of death and disability world- wide. Hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM) often progress to systolic heart failure (HF), the leading cause of death in the U.S. However, the molecular mechanisms underlying these cardiovascular disorders are not fully understood. We identified CIP as a novel cardiac-specific nuclear protein and demonstrated that CIP modulates cardiomyocyte hypertrophy and dilated cardiomyopathy. The overall goal of our study is to uncover the physiological and pathological functions of CIP in the heart and heart diseases.
The specific aims are:
Specific Aim #1. To determine the in vivo function of CIP in the heart.
Specific Aim #2. To test the hypothesis that CIP prevents the progression of HCM to DCM and heart failure.
Specific Aim #3. To define the molecular mechanism by which CIP regulates HCM and DCM. This study will provide important insights into our understanding the molecular events underlying cardiac function and cardiomyopathy and are an important prerequisite to developing therapeutic strategies that correct or circumvent cardiovascular diseases.

Public Health Relevance

Cardiovascular diseases continue to be a leading cause of death and disability. Despite this alarming fact, there is lack of effectual treatment and the molecular mechanisms that regulate these devastating diseases remain elusive. Mammalian heart has minimal regenerative capacity. In response to mechanical or pathological stress, the heart undergoes cardiac remodeling. Pressure and volume overload in the heart often leads to cardiac hypertrophy, an increase in the size of heart and cardiomyocytes. Progression of cardiac hypertrophy and adverse cardiac remodeling often lead to dilated cardiomyopathy (DCM), which displays weakened and enlarged heart and decreased heart function. DCM is the precursor of the end-staged systolic heart failure (HF), which is the leading cause of death in the U.S. The overall goal of our investigation proposed here is to uncover the regulatory circuits in cardiac hypertrophy and dilated cardiomyopathy. This study will provide important insights into our understanding of the molecular events underlying cardiac function and cardiomyopathy. The molecular mechanisms revealed in these studies may apply to pathophysiologically-related cardiac conditions such as human congenital heart defect, hypertrophy, dilated cardiomyopathy and cardiac failure. These studies are an important prerequisite to developing therapeutic strategies that ultimately limit the progression of DCM to HF.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL116919-01A1
Application #
8504611
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Sopko, George
Project Start
2013-07-01
Project End
2017-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
1
Fiscal Year
2013
Total Cost
$416,500
Indirect Cost
$178,500
Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115
Naya, Francisco J; Wang, Da-Zhi (2016) (MYO)SLIDing Our Way Into the Vascular Pool of Long Noncoding RNAs. Arterioscler Thromb Vasc Biol 36:2033-4
Huang, Zhan-Peng; Ding, Yan; Chen, Jinghai et al. (2016) Long non-coding RNAs link extracellular matrix gene expression to ischemic cardiomyopathy. Cardiovasc Res :
Ding, Jian; Chen, Jinghai; Wang, Yanqun et al. (2015) Trbp regulates heart function through microRNA-mediated Sox6 repression. Nat Genet 47:776-83
Huang, Zhan-Peng; Kataoka, Masaharu; Chen, Jinghai et al. (2015) Cardiomyocyte-enriched protein CIP protects against pathophysiological stresses and regulates cardiac homeostasis. J Clin Invest 125:4122-34
Ding, Jian; Wang, Da-Zhi (2015) Mystery of Trbp, tale of a RBP in the miRNA pathway. Cell Cycle 14:3007-8
Nie, Mao; Deng, Zhong-Liang; Liu, Jianming et al. (2015) Noncoding RNAs, Emerging Regulators of Skeletal Muscle Development and Diseases. Biomed Res Int 2015:676575
Wu, Gengze; Cai, Jin; Han, Yu et al. (2014) LincRNA-p21 regulates neointima formation, vascular smooth muscle cell proliferation, apoptosis, and atherosclerosis by enhancing p53 activity. Circulation 130:1452-65
Seok, Hee Young; Chen, Jinghai; Kataoka, Masaharu et al. (2014) Loss of MicroRNA-155 protects the heart from pathological cardiac hypertrophy. Circ Res 114:1585-95
Liu, Jianming; Wang, Da-Zhi (2014) An epigenetic ""LINK(RNA)"" to pathological cardiac hypertrophy. Cell Metab 20:555-7
Espinoza-Lewis, Ramón A; Wang, Da-Zhi (2014) Generation of a Cre knock-in into the Myocardin locus to mark early cardiac and smooth muscle cell lineages. Genesis 52:879-87

Showing the most recent 10 out of 22 publications