TGFb and Cardiac Neural Crest Cell Fate and Function

TGFb 和心脏神经嵴细胞的命运和功能

• 批准号: 7195088
• 负责人: Henry M Sucov
• 金额: $ 39.57万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7195088
• 关键词: Ablation; Address; Aneurysm; Aorta; Apoptosis; Arteries; Behavior; Blood Vessels; Cardiac; Cells; Defect; Deterioration; Development; Diagnostic; Disruption; Distal; Ductus Arteriosus; Elastin Fiber; Embryo; Endoderm; Event; Extracellular Matrix; Failure; Gene Expression; Genes; Heart; Human; Hypoplastic Left Heart Syndrome; Lead; Left; Lung; Maintenance; Mesenchymal; Morphogenesis; Mus; Mutant Strains Mice; Mutation; Neural Crest; Neural Crest Cell; Numbers; Pathway interactions; Penetrance; Persistent Truncus Arteriosus; Phenotype; Pregnancy; Process; Receptor Gene; Research Personnel; Retinoic Acid Receptor; Role; Signal Pathway; Signal Transduction; Smooth Muscle; Smooth Muscle Myocytes; Staging; Stress; Therapeutic; Tissues; Transgenes; Tretinoin; Truncus Arteriosus; aortic arch; ascending aorta; base; cell behavior; computerized data processing; fibrillin; in vitro Assay; knockout gene; malformation; migration; mutant; programs; receptor; response

DESCRIPTION (provided by applicant): This project addresses signaling processes during formation of the aorta and pulmonary trunk, and then in the maturation and maintenance of these vessels. A greater understanding of these processes might lead to diagnostic or therapeutic opportunities for malformations that occur when these processes go awry. We have undertaken neural crest-specific disruption of the type II TGFb receptor gene (Tgfbr2) in mice, to address the role of TGFb signaling in the formation and maturation of the outflow tract vessels of the developing heart. Mutant embryos have persistent truncus arteriosus (PTA) and interrupted aortic arch (IAA- B); later in gestation, the elastic matrix of the neural crest-derived vessel wall of the ductus arteriosus becomes disorganized, leading to vessel wall dilation (aneurysm). The central premise to explain these defects is that the behavior of neural crest cells is dictated by local signaling events, that neural crest cells respond directly to these signals, and that TGFb is one such signal. Specific Aim 1: To identify mechanisms by which absence of TGFb signaling in neural crest cells results in PTA. In this Aim, we will identify and characterize the role of genes that are misregulated in neural crest- derived smooth muscle cells; we will also address the requirement for Smad-dependent signaling pathways downstream of the TGFb receptor. Specific Aim 2: To address the role of retinoic acid and RA receptors in the formation of the A/P septum, and the potential convergence of this pathway with TGFb signaling pathways. Mutation of retinoic acid receptor genes leads to a virtually identical PTA defect as in Tgfbr2 mutants. We will define the tissue in which retinoic acid signaling occurs, and address the convergence of RA and TGFb signaling pathways in the process of outflow tract septation. Specific Aim 3: To address the role of TGFb signaling in vessel wall maturation. In this Aim, we will study the onset of vascular wall deformation, address the extent to which TGFb signal transduction is required in mesodermally-derived vs. neural crest-derived smooth muscle and resolve whether vessel dilation results directly or indirectly from a mechanically impaired vessel wall.

描述（由申请人提供）：该项目涉及主动脉和肺动脉干形成过程中的信号传导过程，然后是这些血管的成熟和维持。对这些过程的更深入了解可能会为这些过程出错时发生的畸形提供诊断或治疗机会。我们已经进行了神经嵴特异性破坏的II型TGF β受体基因（Tgfbr 2）在小鼠中，以解决TGF β信号转导的作用，在形成和成熟的流出道血管的发展心脏。突变胚胎具有持续的动脉干（PTA）和中断的主动脉弓（IAA- B）;在妊娠后期，动脉导管的神经嵴衍生血管壁的弹性基质变得紊乱，导致血管壁扩张（动脉瘤）。解释这些缺陷的中心前提是，神经嵴细胞的行为是由局部信号事件决定的，神经嵴细胞直接对这些信号做出反应，而TGF β就是这样一种信号。具体目标1：确定神经嵴细胞中TGF β信号传导缺失导致PTA的机制。在这个目标中，我们将鉴定和表征在神经嵴来源的平滑肌细胞中被错误调节的基因的作用;我们还将解决TGF β受体下游对Smad依赖性信号传导途径的需求。具体目标二：探讨视黄酸和RA受体在A/P隔形成中的作用，以及该通路与TGF β信号通路的潜在趋同性。视黄酸受体基因突变导致与Tgfbr 2突变体几乎相同的PTA缺陷。我们将定义维甲酸信号发生的组织，并解决RA和TGF β信号通路在流出道分隔过程中的会聚。具体目标3：阐明TGF β信号传导在血管壁成熟中的作用。在这个目标中，我们将研究血管壁变形的发生，解决在中胚层来源的平滑肌与神经嵴来源的平滑肌中需要TGF β信号转导的程度，并解决血管扩张是否直接或间接来自机械受损的血管壁。