Molecular Pathway in Myocardium Development

心肌发育的分子途径

• 批准号: 7469412
• 负责人: WEINIAN SHOU
• 金额: $ 37.38万
• 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/7469412
• 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; Elevation; 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; Localized; 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; Thinking; Transcriptional Activation; Transgenic Mice; Up-Regulation; Ventricular; cell type; design; in vivo; mouse model; mutant; novel; research study; response; size; 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。小梁的显著减少与心肌生长停止密切相关，从而导致早期胚胎死亡。相反，心肌生长异常升高导致心肌压实失败，这被认为是严重的小儿心脏畸形的基础，称为左心室心肌不压实（NLVM）。然而，对于心室小梁和压实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）在心脏中普遍表达，被认为在多种细胞内信号通路中发挥作用，包括通过其与Ca2+释放通道（如IPS受体）和肌细胞中的ryanodine受体的相互作用介导的Ca2+信号传导。有趣的是，fkbp12缺陷小鼠表现出心室超纤和非压实。这些突变小鼠为我们提供了一个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，有一个新的心内膜到心肌信号传递系统调节这一形态发生过程。骨形态发生蛋白-10 （Bmp10）生长因子可能受神经调节蛋白erbb信号网络的控制。此外，FKBP12被发现与内皮钙调磷酸酶- nfatd通路有关。该建议旨在验证我们的假设，即Nrg1-ErbB-Bmp10和钙调神经蛋白- nfatd的遗传网络形成一个关键的信号级联，调节心室小梁和压实的内皮-心肌相互作用。提出了三个具体目标。目的1是验证心内膜内皮分别是fkbp12缺陷心脏室性超调和非压实缺陷的因素的假设。目的2是验证Nrg1上调和NFATcl核表达延长在心内膜内皮细胞中直接导致FKBP12零高束和非压实的假设。目的3是验证小梁限制性BmpIO心肌细胞表达是心内膜-心肌Nrg1-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非压实性疾病的潜在病因。