Ventricular wall formation and maturation require multiple steps that include trabeculation followed by compaction. A significant reduction in trabeculation is closely associated with myocardial growth arrest, which leads to early embryonic lethality. In contrast, abnormal elevation of myocardial growth leads to a failure of myocardial compaction, which is thought to underlie the severe pediatric cardiac malformation, called Noncompaction of the Left Ventricular Myocardium (NLVM). However, little is known about the underlying molecular and cellular mechanisms responsible for ventricular trabeculation and compaction and the pathogenesis of NLVM. FK506 Binding Protein 12 (FKBP12) is ubiquitously expressed in the heart and is thought to play a role in multiple intracellular signaling pathways, including Ca2+mediated signaling via its interaction with Ca2+release channels (e.g. IPS receptor) and the ryanodine receptor in myocytes. Interestingly, FKBP12-deficient mice exhibit ventricular hypertrabeculation and noncompaction. These mutant mice provide us with a unique mouse model to investigate ventricular wall maturation and the mechanisms that are responsible for NLVM. Our preliminary data suggest that there is a novel endocardium- to-myocardium signaling relay system regulating this morphogenetic process. A trabecular-restricted Bone Morphogenetic Protein-10 (Bmp10) growth factor is potentially controlled by neuregulin-ErbB signaling network. Additionally, FKBP12 was found to be linked to endothelial calcineurin-NFATd pathway. This proposal is designed to test our hypothesis that there is a genetic network of Nrg1-ErbB-Bmp10 and calcineurin-NFATd that form a key signaling cascade that regulates endothelial-myocardial interactions for ventricular trabeculation and compaction.
Three specific aims are proposed.
Aim 1 is to test the hypothesis that endocardial endothelium is the respective contributor to ventricular hypertrabeculation and noncompaction defects in FKBP12-deficient heart.
Aim 2 is to test the hypothesis that up-regulatiori of Nrg1 and prolonged nuclear expression of NFATcl in the endocardial endothelial cells are directly responsible for FKBP12 null hypertrabeculation and noncompaction.
Aim 3 is to test the hypothesis that trabecular-restricted BmpIO cardiomyocyte expression is a downstream target for endocardium-to-myocardium Nrg1-ErbB signaling network. Our research will help to uncover potential etiology for cardiac noncompaction disease. ? ? ?
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