Molecular Pathway in Myocardium Development

心肌发育的分子途径

• 批准号: 7793581
• 负责人: WEINIAN SHOU
• 金额: $ 37.36万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-16 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7793581
• 关键词: Affect; Architecture; Biological Assay; Blood; Bone Morphogenetic Protein 10; Calcineurin; Cardiac; Cardiac Myocytes; Cell Count; Childhood; Conditioned Culture Media; Congenital Heart Defects; Data; Defect; Development; Disease; Embryo; Embryonic Development; Embryonic Heart; Endocardium; Endothelial Cells; Endothelium; ErbB4 gene; Etiology; Exhibits; Failure; Gene Expression Profile; Genes; Genetic; Goals; Growth; Growth Factor; Heart; Image Analysis; In Vitro; Knock-out; Knockout Mice; Left; Link; Mediating; Molecular; Molecular Analysis; Mus; Muscle Cells; Mutant Strains Mice; Myocardial; Myocardium; Nature; Neuregulin 1; Neuregulins; Nuclear; Pathogenesis; Pathway interactions; Play; Process; Regulation; Research; Role; Ryanodine Receptor Calcium Release Channel; Ryanodine Receptors; Series; Signal Pathway; Signal Transduction; Solid; Staging; System; Tacrolimus Binding Proteins; Testing; Transgenic Mice; Up-Regulation; Ventricular; cell type; design; in vivo; mouse model; mutant; novel; receptor; research study; response; spatiotemporal

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.

描述（由申请人提供）：心室壁的形成和成熟需要多个步骤，包括小梁形成和压实。小梁的显着减少与心肌生长停滞密切相关，从而导致早期胚胎死亡。相反，心肌生长的异常升高会导致心肌致密化失败，这被认为是严重的儿科心脏畸形的基础，称为左心室心肌致密化不全（NLVM）。然而，人们对心室小梁形成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 (FKBP12) 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 Ca2+ 释放通道（例如 IPS 受体）和肌细胞中的兰尼碱受体相互作用而介导的 Ca2+ 信号传导。有趣的是，FKBP12 缺陷小鼠表现出心室小梁过度和致密化不全。这些突变小鼠为我们提供了一种独特的小鼠模型来研究心室壁成熟和 NLVM 的机制。我们的初步数据表明，存在一种新型的心内膜到心肌信号传递系统调节这种形态发生过程。小梁限制性骨形态发生蛋白 10 (Bmp10) 生长因子可能受神经调节蛋白-ErbB 信号网络控制。此外，发现 FKBP12 与内皮钙调神经磷酸酶-NFATd 通路相关。该提案旨在检验我们的假设，即 Nrg1-ErbB-Bmp10 和钙调神经磷酸酶-NFATd 的遗传网络形成关键的信号级联，调节心室小梁和压缩的内皮-心肌相互作用。提出了三个具体目标。目标 1 是检验以下假设：心内膜内皮是 FKBP12 缺陷心脏中心室小梁过度和致密化缺陷的各自贡献者。目标 2 是检验以下假设：心内膜内皮细胞中 Nrg1 的上调和 NFATcl 的核表达延长直接导致 FKBP12 无效的小梁过度化和致密化不全。目标 3 是检验以下假设：小梁限制性 BmpIO 心肌细胞表达是心内膜到心肌 Nrg1-ErbB 信号网络的下游靶标。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。