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.
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.
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