Ventricular trabeculation and compaction are two distinct but related morphogenetic events that are essential for normal ventricular myocardial wall development. Dysregulation of these events can lead to Left Ventricular Noncompaction (LVNC, MIM300183 and 604169). LVNC is an inherited cardiomyopathy, and is clinically defined by persistent LV trabeculae, increased inter-trabecular recesses, and thin LV walls, particularly at the apex. LVNC is often associated with other congenital heart diseases (CHDs). The etiology and pathogenesis of LVNC are elusive due to the genetic heterogeneity of the patients and the overall lack of understanding of the molecular mechanisms orchestrating ventricular trabeculation and compaction. Previously, we have generated a number of genetically modified mouse models which exhibit LVNC. Collectively these studies suggest a hypothesis wherein Dishevelled-associated activator of morphogenesis 1 (Daam1) plays a key regulatory role in directing compaction of the ventricular wall. Daam1 is an effector of non-canonical Wnt Planer Cell Polarity (PCP) signaling and impacts actin polymerization, and Daam1 genetic ablation leads to ventricular noncompaction. We hypothesized that Daam1-mediated signaling is critical to establish cardiomyocyte polarity, sarcomere maturation, and through this process regulates ventricular wall compaction. Project 3 builds upon these findings and will directly address the aforementioned hypothesis. Experiments proposed in Aim 1 will delineate the molecular pathways which give rise to positive and negative regulation of Daam1 activity, and determine their impact on ventricular wall compaction. Experiments proposed in Aim 2 will examine a number of additional LVNC mouse models and test the hypothesis that Daam1-mediated loss of cardiomyocyte polarity constitutes a common underlying molecular etiology for the genesis of LVNC. Collectively, the experiments proposed in Project 3 will provide insight into how ventricular compaction is regulated, establishing novel understanding of signaling pathways that when disrupted result in the pathogenesis of LVNC in mice and potentially in humans.

Public Health Relevance

There has been increasing clinical awareness in the past 15 years of a new form of inherited cardiomyopathy- left ventricular noncompaction (LVNC, MIM 300183). This proposal will expand and refine our on-going efforts to establish the molecular signaling pathways regulating normal trabeculation and compaction of the myocardium and the potential pathogenetic pathways that lead to LVNC.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
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Heart, Lung, and Blood Initial Review Group (HLBP)
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Schramm, Charlene A
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Indiana University-Purdue University at Indianapolis
United States
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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
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
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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