Molecular Pathway in Myocardium Development

描述（由申请人提供）：心室壁形成和成熟需要多个步骤，包括小梁形成和随后的致密化。小梁形成的显著减少与心肌生长停滞密切相关，这导致早期胚胎死亡。相反，心肌生长的异常升高导致心肌致密化失败，这被认为是严重的小儿心脏畸形的基础，称为左心室心肌致密化不全（NLVM）。然而，对心室小梁形成和致密化的分子和细胞机制以及NLVM的发病机制知之甚少。FK 506结合蛋白12（FKBP 12）在心脏中广泛表达，被认为在多种细胞内信号传导途径中发挥作用，包括通过与肌细胞中的Ca 2+释放通道（例如IPS受体）和兰尼碱受体相互作用的Ca 2+介导的信号传导。有趣的是，FKBP 12缺陷型小鼠表现出心室小梁形成过度和致密化不全。这些突变小鼠为我们提供了一个独特的小鼠模型，以研究心室壁成熟和NLVM的机制。我们的初步数据表明，有一个新的内皮细胞到心肌信号中继系统调节这一形态发生过程。骨小梁限制性骨形态发生蛋白-10（Bmp 10）生长因子可能受神经调节蛋白-ErbB信号网络控制。此外，发现FKBP 12与内皮钙调神经磷酸酶-NFATd途径相关。该提议旨在验证我们的假设，即存在Nrg 1-ErbB-Bmp 10和钙调神经磷酸酶-NFATd的遗传网络，其形成调节心室小梁形成和致密化的内皮-心肌相互作用的关键信号级联。提出了三个具体目标。目的1是检验内皮细胞是FKBP 12缺陷心脏中心室过度小梁形成和致密化不全缺陷的各自贡献者的假设。目的2是验证以下假设：内皮细胞中Nrg 1的上调和NFATc 1的延长的核表达是FKBP 12无效的过度小梁形成和致密化不全的直接原因。目的3是验证小梁限制的BmpIO心肌细胞表达是心内膜-心肌Nrg 1-ErbB信号网络的下游靶点的假设。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.