Molecular Pathway in Myocardium Development

描述(申请人提供)：室壁的形成和成熟需要多个步骤，包括小梁形成和紧实化。小梁形成的显著减少与心肌生长停滞密切相关，心肌生长停滞会导致早期胚胎死亡。相反，心肌生长异常升高会导致心肌致密化失败，这被认为是儿童严重心脏畸形的基础，称为左心室心肌致密化不全(NLVM)。然而，对导致脑室小梁和致密化的潜在分子和细胞机制以及NLVM的发病机制知之甚少。FK506结合蛋白12(FK506 Binding Protein 12，FKBP12)在心脏中广泛表达，参与多种细胞内信号转导途径，包括通过与钙释放通道(如IPS受体)和兰尼定受体相互作用介导的细胞内信号转导。有趣的是，FKBP12基因缺陷的小鼠表现出心室过度小梁和致密化不全。这些突变的小鼠为我们提供了一个独特的小鼠模型来研究室壁成熟和导致NLVM的机制。我们的初步数据表明，存在一种新的心内膜到心肌的信号传递系统来调节这一形态发生过程。骨小梁限制性骨形态发生蛋白-10(Bmp10)生长因子受NeuRegin-ErbB信号网络的潜在调控。此外，还发现FKBP12与内皮细胞钙调神经磷酸酶-NFATd通路有关。这一建议旨在检验我们的假设，即存在一个由Nrg1-ErbB-Bmp10和Calcineurin-NFATd组成的遗传网络，形成一个关键的信号级联，调节血管内皮细胞与心肌之间的相互作用，从而促进心室的小梁形成和压缩。提出了三个具体目标。目的1验证心内膜内皮细胞是FKBP12缺陷心脏的室壁过度小梁形成和致密化不全的诱因的假说。目的2验证Nrg1上调和NFATc1在心内膜内皮细胞中的核表达延长与FKBP12缺失的过度小梁和致密不全直接相关的假说。目的3验证小梁限制性BmpIO心肌细胞表达是心内膜到心肌Nrg1-ErbB信号网络下游靶点的假设。我们的研究将有助于揭示心脏致密化不全疾病的潜在病因。

DESCRIPTION (provided by applicant): 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.