Congenital heart disease (CHD) is the most common birth defect. Among various CHDs, single ventricle phenotypes resulting from altered ventricular morphogenesis have the poorest clinical prognoses. CHDs that present with defective ventricular morphogenesis allow for the mixing of oxygenated and deoxygenated blood via ventricular septal defects (VSDs) and/or impaired contractile function both of which put limits on vitality. Currently, there is a poor understanding of the molecular mechanisms and cellular etiology causative of the many forms of ventricular CHDs. Hand1 is expressed within the developing left ventricle (LV) myocardium and the myocardial cuff (MC) between embryonic day (E) E8.5 and E13.5. Gene targeting models establish that Hand1 is required for normal LV development. We show that cardiomyocyte deletion of Hand1 results in surviving mice that present with CHDs effecting LV morphology. Recently, HAND1 mutations have been identified in patients diagnosed with CHDs. These HAND1 gene mutations manifest as frameshift or nonsense mutations within the protein coding domains and are reported to be somatic in nature, as germline mutations in HAND1 are assumed to be embryonic lethal. Like all genes, Hand1 is transcriptionally regulated through cis-element enhancers located within Conserved Non-coding Sequences (CNS) that are present both 5' and 3' to the Hand1 transcriptional start site. The notion that CNS gene mutations affecting the function of Hand1 through defects in cardiac transcriptional regulatory elements is a largely unexplored hypothesis that could provide a mechanism for heritable Hand1 cardiac loss-of-function in human CHDs.

Public Health Relevance

CHDs resulting in ventricle phenotypes have the poorest clinical outcomes. Thus, gaining an understanding of the etiology and molecular mechanisms that cause CHDs resulting in altered ventricular morphogenesis has the potential to benefit thousands of pediatric patients annually. Hand1 plays a key role in cardiomyocyte patterning and gaining insight into the cellular and molecular mechanism of this understudied developmental process will have a great benefit to developing non-surgical treatments for CHD patients.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL134599-03
Application #
9640230
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Schramm, Charlene A
Project Start
Project End
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
Type
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
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
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
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

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