Congenital heart defects (CHDs) are the most commonly encountered birth defect, affecting as many as 8 in 1,000 live births. In many cases, life-saving surgical intervention is required. Despite the prevalence, in many cases the underlying molecular etiology of CHDs is not known. The central theme of this Program Project Grant application is to elucidate mechanisms that regulate growth and morphogenesis of the ventricle during development. Our objective is to gain understanding of how early events impacting mesoderm-lineage specification and differentiation, how mid-gestational events impacting septation and papillary muscle formation, and how late-gestational events impacting cardiomyocyte polarity and sarcomere maturation each contribute to normal ventricular morphogenesis. Three highly interactive and complementary Projects are proposed to attain these objectives. Project 1 will study the molecular mechanisms contributing to the genesis of CHDs in an animal model of X-linked heterotaxy. These studies build on work from Dr. Stephanie Ware's laboratory and will test the overall hypothesis that morphogenic defects in early embryonic structures can impact the migration and differentiation of primitive progenitor cells which subsequently give rise to the myocardium. Such a mechanism would explain why the spectrum of CHDs encountered in heterotaxia patients is more severe than what would be anticipated to result from altered sidedness. Project 2 will study the molecular mechanisms regulating ventricular septation and papillary muscle formation. These studies build on work from Dr. Anthony Firulli's laboratory and will test the overall hypothesis that expression cardiomyogenic transcription factors imparts morphogenic cues directing normal cardiomyocyte patterning in the developing left ventricle, and that mid-gestational alteration of this patterning gives rise to CHD. Such a mechanism would establish cell and molecular pathways which regulate normal and abnormal development of the ventricular septation and papillary muscle. Project 3 will study the molecular mechanisms regulating compaction of the left ventricle during cardiac development. These studies build on work from Dr. Weinian Shou's laboratory and will test the overall hypothesis that altered cardiomyocyte cell polarity gives rise to ventricular noncompaction, and furthermore, will dissect the molecular regulatory cascades which are required to establish normal cardiomyocyte polarity. Such a mechanism would establish a common underlying molecular etiology which gives rise to left ventricular noncompaction. The proposed work will be facilitated by the participation of three cores (Administration, Cardiac Imaging and Mouse Resources). Ultimately, the studies proposed in this Program Project Grant application will illustrate how events occurring prior to overt heart formation, during early cardiac development, and during late maturation of the ventricular wall are sequentially integrated for normal cardiac morphogenesis. Importantly, defining the molecular regulation of these events will provide insight into potential interventions aiming to mitigate the deleterious impact of CHD.

Public Health Relevance

The proposed research is important because increasing evidence demonstrates that cardiomyopathies and congenital heart defects are a significant public burden; however, the mechanisms by which this occurs are poorly understood. Research in this area is crucial to both prevention and treatment, and therefore this research proposal addresses an important human health problem aligned with the mission of the NHLBI at the NIH.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL134599-03
Application #
9640221
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Schramm, Charlene A
Project Start
2017-02-15
Project End
2022-01-31
Budget Start
2019-02-01
Budget End
2020-01-31
Support Year
3
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Pediatrics
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Xiao, Yun-Fei; Zeng, Zhi-Xiong; Guan, Xiao-Hui et al. (2018) FKBP12.6 protects heart from AngII-induced hypertrophy through inhibiting Ca2+ /calmodulin-mediated signalling pathways in vivo and in vitro. J Cell Mol Med 22:3638-3651
Wang, Jun; Shen, Tao; Zhu, Wuqiang et al. (2018) Protein phosphatase 5 and the tumor suppressor p53 down-regulate each other's activities in mice. J Biol Chem 293:18218-18229
Liu, Ying; Chen, Vincent H S; Shou, Weinian (2018) LUMA in cardiac development and function. Cardiovasc Res 114:347-348
Shi, Jianjian; Surma, Michelle; Wei, Lei (2018) Disruption of ROCK1 gene restores autophagic flux and mitigates doxorubicin-induced cardiotoxicity. Oncotarget 9:12995-13008
Miao, Lianjie; Li, Jingjing; Li, Jun et al. (2018) Notch signaling regulates Hey2 expression in a spatiotemporal dependent manner during cardiac morphogenesis and trabecular specification. Sci Rep 8:2678
Xiao, Deyong; Wang, Huijun; Hao, Lili et al. (2018) The roles of SMYD4 in epigenetic regulation of cardiac development in zebrafish. PLoS Genet 14:e1007578
Liu, Ying; Chen, Hanying; Shou, Weinian (2018) Potential Common Pathogenic Pathways for the Left Ventricular Noncompaction Cardiomyopathy (LVNC). Pediatr Cardiol 39:1099-1106
Martinez, Hugo R; Ware, Stephanie M; Schamberger, Marcus S et al. (2017) Noncompaction cardiomyopathy and heterotaxy syndrome. Prog Pediatr Cardiol 46:23-27
Ware, Stephanie M (2017) Genetics of paediatric cardiomyopathies. Curr Opin Pediatr 29:534-540
Vincentz, Joshua W; Toolan, Kevin P; Zhang, Wenjun et al. (2017) Hand factor ablation causes defective left ventricular chamber development and compromised adult cardiac function. PLoS Genet 13:e1006922

Showing the most recent 10 out of 11 publications