In Vivo Analysis of the Mechanisms of Neural Crest Migration

神经嵴迁移机制的体内分析

基本信息

批准号：
8134840
负责人：
PAUL KULESA
金额：
$ 32.11万
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：
2008
资助国家：
美国
起止时间：
2008-09-30 至 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8134840
关键词：
Address Affect Behavior Biological Cardiovascular Physiology Cardiovascular system Cell Communication Cell Lineage Cells Cellular Morphology Cephalic Chick Embryo Complex Congenital Abnormality Cues Data Defect Development Developmental Biology Embryo Ensure Enteric Nervous System Environment Exclusion Goals Image Individual Invaded Knowledge Label Laboratories Life Microsurgery Modeling Molecular Neural Crest Neural Crest Cell Neuropilins Organ Pathway interactions Pattern Peripheral Phenotype Play Population Positioning Attribute Role Semaphorins Signal Pathway Signal Transduction Speed Stem cells Stream Structure Subgroup Testing Tissue Transplantation Translating Vascular Endothelial Growth Factors base cell behavior cell motility cellular imaging craniofacial in vivo in vivo Model insight migration novel novel therapeutics photoactivation prevent public health relevance tool

项目摘要

DESCRIPTION (provided by applicant): One of the most devastating birth defects affect the neural crest, a highly migratory stem cell-like population that contribute to craniofacial and cardiovascular development, and peripheral and enteric nervous system assembly. Cell lineage tracing and tissue transplantation studies have revealed the neural crest cell (NCC) migratory pathways emerge as discrete segregated streams, separated by neural-crest-free exclusion zones that appear to prevent the intermixing of NCC subpopulations and ensure their arrival at precise targets. These findings support the premise that neural crest cell guidance cues derive from the embryonic microenvironment and cell communication. Most noteworthy are the data we have generated in vivo showing cell-cell and cell-environment interactions may influence the directional migration of the neural crest. Based on these observations, we propose to test the central hypothesis that the microenvironment and cell-cell interactions associated with the neural crest-rich regions of the embryo contain informational cues with the potential to direct cells to precise targets. Our long term goal is to understand the biological mechanisms underlying neural crest migration that ultimately results in organ development. Our short term goal is to identify the key cellular and molecular mechanisms underlying the sculpting of cranial NCC migratory streams within an in vivo model. Using in vivo molecular perturbations and embryo microsurgery, together with photoactivation cell labeling, 4-D confocal imaging, cell tracking and cell behavior analyses, we propose to: Aim 1: Characterize the specific and dynamic cellular interactions essential for cranial neural crest migration using in vivo photoactivation cell labeling, 4-D confocal imaging, cell tracking and cell behavior analyses. Aim 2: To determine the role of neuropilins within the embryonic microenvironment in signaling and modulating neural crest migration. Aim 3: Investigate the role of the embryonic microenvironment in signaling and modulating neural crest migration, with particular focus on neuropilin- semaphorin and neuropilin-VEGF interactions. Public Health Relevance: At the completion of these studies, we expect to have an increased understanding of guidance cues and pathways that directly modulate neural crest migration that could be translated for novel therapeutic applications.

描述（由申请人提供）：最具破坏性的出生缺陷之一影响神经嵴，这是一种高度迁移的干细胞样群，有助于颅面和心血管发育以及周围和肠神经系统的组装。细胞谱系追踪和组织移植研究表明，神经嵴细胞 (NCC) 迁移途径以离散的隔离流形式出现，并被无神经嵴的禁区分隔开，这些禁区似乎可以防止 NCC 亚群的混合并确保它们到达精确的目标。这些发现支持这样的前提：神经嵴细胞引导信号源自胚胎微环境和细胞通讯。最值得注意的是我们在体内生成的数据显示细胞-细胞和细胞-环境相互作用可能影响神经嵴的定向迁移。基于这些观察，我们建议检验中心假设，即与胚胎神经嵴丰富区域相关的微环境和细胞间相互作用包含信息线索，有可能引导细胞到达精确的目标。我们的长期目标是了解最终导致器官发育的神经嵴迁移的生物学机制。我们的短期目标是确定体内模型中颅内 NCC 迁移流塑造的关键细胞和分子机制。利用体内分子扰动和胚胎显微手术，以及光激活细胞标记、4-D 共聚焦成像、细胞追踪和细胞行为分析，我们建议：目标 1：表征颅神经嵴迁移所必需的特定和动态细胞相互作用体内光激活细胞标记、4-D 共焦成像、细胞追踪和细胞行为分析。目标 2：确定胚胎微环境中神经毡蛋白在信号传导和调节神经嵴迁移中的作用。目标 3：研究胚胎微环境在信号传导和调节神经嵴迁移中的作用，特别关注神经毡蛋白-脑信号蛋白和神经毡蛋白-VEGF 相互作用。公共卫生相关性：在完成这些研究后，我们期望对直接调节神经嵴迁移的指导线索和途径有更多的了解，这些指导线索和途径可以转化为新的治疗应用。