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Role of Slit molecules in neural crest delamination

狭缝分子在神经嵴分层中的作用

基本信息

批准号：
8811898
负责人：
Maria Elena de Bellard
金额：
$ 41.48万
依托单位：
CALIFORNIA STATE UNIVERSITY NORTHRIDGE
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-07-01 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8811898
关键词：
Affect Attenuated Biological Assay Brain Cartoons Cell Line Cell Proliferation Cell physiology Cells Cellular biology Complex Cyclins Cytoskeletal Modeling Cytoskeleton Development Developmental Cell Biology Developmental Process Docking Dorsal Electroporation Epithelial Event Fibroblast Growth Factor Fluorescence Genomics Goals Grant In Situ In Situ Hybridization In Vitro Knowledge Maintenance Malignant Neoplasms Mesenchymal Mesenchymal Stem Cells Methods Molecular Molecular Biology Neoplasm Metastasis Neural Crest Neural Crest Cell Neural tube Neuroepithelial Neurons Outcomes Research Pathway interactions Phenotype Play Polycomb Population Process Proliferating Role Signal Transduction Snails Stem cells Students TFAP2A gene Techniques Tumor Suppressor Genes Tumor Suppressor Proteins Work axonal guidance beta catenin cancer cell cdc Genes cell motility epithelial to mesenchymal transition gain of function inhibitor/antagonist insight loss of function migration migratory population neoplastic cell nerve stem cell neuroepithelium notch protein novel strategies prevent progenitor public health relevance research study rho rho GTP-Binding Proteins transcription factor tumor tumor progression

项目摘要

DESCRIPTION (provided by applicant): The neural crest provides a unique population of migratory stem cells with which to study a variety of cell and neural developmental processes. Neural crest cells emerge from the neuroepithelium in development and transform into a mesenchymal/migratory population. Several inhibitory molecules have been shown to play important roles in neural crest migration including the chemorepulsive molecules Slit 1-3. Slit molecules were initially discovered as axonal guidance molecules; however, recently they have been also shown to be true tumor suppressors and affect cell proliferation in cancer cells. Neural crest cell migration has been repeatedly likened to the process of cancer metastasis and cell invasion. Slit molecules attenuate cancer progression by regulating beta-catenin expression and are also able to negatively regulate metastasis. Results from our previous grant demonstrated that Slit chemorepellant molecules impair neural crest cell migration and alters neural crest cells cytoskeletal organization towards a non- migratory phenotype. However, we still do not know the precise role that Slit molecules play on pre-migratory neural crest cells. Do Slit molecules prevent neural crest delamination in a manner analogous to the way Slits prevent tumor metastasis? If so, what are the molecular mechanisms that allow Slit molecules to prevent the delamination of the pre-migratory neural crest cells? Do Slits modulate pre-migratory neural crest cell proliferation? The significance of this proposal is that it will determne whether or not Slits have an effect on neural crest delamination during the epithelial-to- mesenchymal transition (EMT) via their "tumor suppressor mechanisms" and/or if Slits modulate pre-migratory neural crest proliferation. The approach of this new proposal is to study of the role of Slit molecules in the pre-migratory neural crest cell using cell biology and genomic methods. The findings from this project will: 1) expand the current knowledge on the role of the tumor suppressor Slits in neural crest cell proliferation; 2) determine if pre-migratory neural crest cels need to silence Slits before delamination; and, 3) provide insight into tumor suppressor activity by elucidating the role of Slits in cell migration.

描述（由申请人提供）：神经嵴提供了独特的迁移干细胞群，用于研究各种细胞和神经发育过程。神经嵴细胞从发育中的神经上皮中出现，并转化为间充质/迁移细胞群。几种抑制分子已被证明在神经嵴迁移中发挥重要作用，包括化学脉冲分子 Slit 1-3。狭缝分子最初被发现是作为轴突引导分子；然而，最近它们也被证明是真正的肿瘤抑制剂并影响癌细胞的细胞增殖。神经嵴细胞迁移被多次比作癌症转移和细胞侵袭的过程。 Slit 分子通过调节 β-连环蛋白的表达来减弱癌症的进展，并且还能够负向调节转移。我们之前资助的结果表明，Slit 化学排斥剂分子会损害神经嵴细胞迁移，并将神经嵴细胞的细胞骨架组织改变为非迁移表型。然而，我们仍然不知道 Slit 分子对迁移前神经嵴细胞的确切作用。做狭缝分子防止神经嵴分层的方式类似于狭缝防止肿瘤转移的方式？如果是这样，Slit分子阻止迁移前神经嵴细胞分层的分子机制是什么？狭缝是否调节迁移前神经嵴细胞增殖？该提案的意义在于，它将确定Slits是否通过其“肿瘤抑制机制”对上皮间质转化（EMT）期间的神经嵴分层产生影响和/或Slits是否调节迁移前神经嵴增殖。这项新提案的方法是研究角色使用细胞生物学和基因组方法对迁移前神经嵴细胞中的狭缝分子进行研究。该项目的研究结果将：1）扩展目前对肿瘤抑制因子 Slits 在神经嵴细胞增殖中的作用的认识； 2)确定迁移前的神经嵴细胞在分层前是否需要沉默Slits； 3) 通过阐明 Slits 在细胞迁移中的作用，深入了解肿瘤抑制活性。