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In Vivo Analysis of TrkB Signaling During Sympathetic Nervous System Development and Neuroblastoma Pathogenesis

交感神经系统发育和神经母细胞瘤发病机制中 TrkB 信号传导的体内分析

基本信息

批准号：
8873369
负责人：
PAUL KULESA
金额：
$ 24.75万
依托单位：
STOWERS INSTITUTE FOR MEDICAL RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-02-01 至 2017-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8873369
关键词：
Address Adrenal Glands Affect Aorta Behavioral Biological Assay Birds Blood Cancer Model Cell Lineage Cell Transplants Cells Complex Congenital Abnormality Data Development Disease Dorsal Drosophila genus Embryo Exposure to Failure Genes Genotype Homeostasis Human Human Development Image Imagery In Situ Individual Infant Laboratories Lead Life Malignant Neoplasms Modeling Molecular Molecular Profiling Molecular Target Mus Neural Crest Neural Crest Cell Neural tube Neuroblastoma Neuroendocrine Cell Neurons Pathogenesis Pathway interactions Pattern Pediatric Neoplasm Peripheral Nervous System Phenotype Quail Reaction Regulation Role Screening for Neuroblastoma Signal Transduction Spinal Cord Sympathetic Ganglia Sympathetic Nervous System Techniques Technology Testing Time Transgenic Organisms Transplantation Zebrafish cell behavior cell motility comparative in vivo in vivo Model in vivo imaging inhibitor/antagonist innovation migration nervous system development neuroblast neuroblastoma cell neurodevelopment neurogenesis novel precursor cell public health relevance research study response spine bone structure success targeted imaging trait tumor

项目摘要

DESCRIPTION (provided by applicant): The molecular and cellular interactions that orchestrate the patterning of the vertebrate peripheral nervous system have yet to be fully elucidated. Upon delamination from the neural tube, trunk neural crest cells destined to form the vertebral chain of sympathetic ganglia migrate ventrally to the vicinity of the dorsal aorta where they aggregate and condense to form the primary chain of sympathetic ganglia composed of differentiated sympathetic neurons and precursor cells. Failure of the neural crest cells to properly migrate and differentiate may result in birth defects and lead to neuroblastoma, a pediatric tumor. of the peripheral nervous system that arises from sympatho-adrenal lineages of the neural crest. Unfortunately, the lack of information about normal development of the sympathetic nervous system and how mis-regulation of signals transform the normal neuroblast to neuroblastoma has severely limited early neuroblastoma detection and treatment, making this disease often fatal in infants. We propose to study sympathetic nervous system development and neuroblastoma pathogenesis using state- of-the-art in vivo imaging in living avian embryos. We discovered a novel role for TrkB signaling during sympathetic neurogenesis, which strikingly has recently been associated with aggressive neuroblastomas. We hypothesize that TrkB signals regulate the plasticity and invasive ability of the neural crest during sympathetic nervous system development at a critical time period when the early transformation from normal neuroblast to neuroblastoma occurs. To test this hypothesis we will determine the functional role of TrkB signaling in sympathetic nervous system development and develop a quail embryo model for neuroblastoma pathogenesis. Quail embryos allow transplantation and visualization of individual human neuroblastoma cell behaviors, a technique pioneered in our laboratory. We recently discovered that human neuroblastoma cells transplanted into the avian embryo follow host neural crest pathways and do not form tumors. The success of this proposal will have a direct impact on neural development and neuroblastoma cancer by providing: (i) critical information on the in vivo role of TrkB signaling during sympathetic neurogenesis and in the early transition from normal neuroblast to neuroblastoma; (ii) an in vivo model to rapidly assay the plasticity and invasiveness of neuroblastoma cells and response to potential inhibitors.

描述（由申请人提供）：协调脊椎动物周围神经系统模式的分子和细胞相互作用尚未完全阐明。从神经管脱层后，注定要形成交感神经节椎链的躯干神经嵴细胞向腹侧迁移到背主动脉附近，在那里它们聚集并凝结形成由分化的交感神经元和前体细胞组成的交感神经节初级链。神经嵴细胞无法正确迁移和分化可能会导致出生缺陷并导致神经母细胞瘤（一种小儿肿瘤）。周围神经系统由神经嵴的交感肾上腺谱系产生。不幸的是，缺乏关于交感神经系统正常发育以及信号调节错误如何将正常神经母细胞转化为神经母细胞瘤的信息，严重限制了早期神经母细胞瘤的检测和治疗，使得这种疾病在婴儿中常常致命。我们建议使用最先进的活禽胚胎体内成像技术来研究交感神经系统发育和神经母细胞瘤发病机制。我们发现了 TrkB 信号在交感神经发生过程中的新作用，该作用最近与侵袭性神经母细胞瘤显着相关。我们假设 TrkB 信号在交感神经活动期间调节神经嵴的可塑性和侵袭能力系统发育处于从正常神经母细胞早期转变为神经母细胞瘤的关键时期。为了检验这一假设，我们将确定 TrkB 信号在交感神经系统发育中的功能作用，并开发神经母细胞瘤发病机制的鹌鹑胚胎模型。鹌鹑胚胎可以移植并可视化单个人类神经母细胞瘤细胞的行为，这是我们实验室首创的技术。我们最近发现，移植到禽胚胎中的人类神经母细胞瘤细胞遵循宿主神经嵴通路，并且不会形成肿瘤。该提案的成功将通过提供以下内容对神经发育和神经母细胞瘤癌症产生直接影响：（i）关于 TrkB 信号在交感神经发生期间以及从正常神经母细胞到神经母细胞瘤的早期转变过程中体内作用的关键信息； (ii) 快速测定神经母细胞瘤细胞的可塑性和侵袭性以及对潜在抑制剂的反应的体内模型。