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Neural Crest Cell Survival and Migration in Zebrafish

斑马鱼神经嵴细胞的存活和迁移

基本信息

批准号：
7393681
负责人：
Rodney A. Stewart
金额：
$ 9万
依托单位：
DANA-FARBER CANCER INST
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 2009-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7393681
关键词：
Address Animals Apoptosis Appointment Behavior Biochemistry Blood Circulation Blood capillaries Cadherins Cell Adhesion Molecules Cell Death Cell Survival Cell-Cell Adhesion Cells Data Defect Development Distant Dorsal E-Cadherin Embryo Endothelium Environment Epithelial Event Faculty Family Family member Gene Expression Genes Genetic Genetic Epistasis Glioma Goals Human Human Genome Immigration Knowledge Label Laboratories Link Malignant Neoplasms Mediating Mediator of activation protein Mentors Mesenchymal Modeling Molecular Mus Mutation Neoplasm Metastasis Neural Crest Neural Crest Cell Neural tube Neurobiology Neuroblastoma Oncogenic Organ Orthologous Gene Pathway interactions Peripheral Peripheral Nerve Sheath Neoplasm Phenocopy Phenotype Process Proliferating Property Protein Overexpression Proteins Puma RNA Research Research Personnel Role Siblings Signal Transduction Site Snails Staging Stem cells Sympathetic Nervous System Synteny System Testing Tissues Transcription factor genes Tumor-Derived Zebrafish base cancer cell capillary cell motility design in vivo melanoma member migration mutant neoplastic cell novel null mutation oncology progenitor programs slug tool transcription factor tumor

项目摘要

DESCRIPTION (provided by applicant) This proposal is designed to provide the candidate a 1-2 year period of mentored research in the laboratory of Dr. A. T. Look (at the Dana Farber), a pioneer in the use of zebrafish as a model to study development of the peripheral sympathetic nervous system and neuroblastoma. This proposal is also designed to support the candidate as an independent investigator during the first 3 years of a new faculty appointment in a neurobiology/oncology department. The goal of this application is to use the zebrafish as a model to dissect the molecular components of Foxd3-mediated neural crest cell survival and migration and to determine if this pathway promotes metastasis of neural crest-derived tumors in vivo. The zebrafish, with its close synteny to the human genome and its conserved molecular pathways regulating the development of tissues and organs, offers a powerful tool with which to conduct such research. The candidate has identified and characterized a zebrafish mutant Foxd3 line that has specific neural crest cell survival and migration defects and has identified the Snail b transcription factor as a critical mediator of Foxd3 function. The underlying hypothesis of this application is that knowledge of the Foxd3 pathway will provide an understanding of how neural crest cells migrate and survive in foreign environments, a requirement for the metastasis of neural crest-derived tumors. In Aim 1, genetic epistasis and biochemistry will determine if Foxd3 directly activates snail b expression in neural crest cells, and whether Snail b represses apoptosis and cell migration by repressing the expression of the promising candidates, puma and e-cadherin, respectively. In Aim 2, GFP-labeled neural crest cells from Foxd3 mutant and wild-type siblings will be analyzed by microarray to identify and analyze additional downstream targets of Foxd3-mediated neural crest cell survival and migration. In Aim 3, Foxd3 and snail b will be over-expressed in developing neural crest cells to examine their potential roles in promoting metastasis in established zebrafish neural crest tumor models. During normal development, cells from the neural tube detach, activate survival programs and migrate to distant regions of the embryo. This process is similar to the way cells behave during metastasis in human cancers. The goal of this application is to find the genes involved in the normal embryonic survival and migration programs and determine if these genes are aberrantly activated during cancer metastasis.

描述（由申请人提供）该计划旨在为候选人提供1-2年的指导研究在实验室的博士。T.看看达纳·法伯（Dana Farber），他是利用斑马鱼作为模型研究外周交感神经系统和神经母细胞瘤发育的先驱。该提案还旨在支持候选人在神经生物学/肿瘤学系新教师任命的前3年担任独立研究员。本申请的目的是使用斑马鱼作为模型来剖析Foxd 3介导的神经嵴细胞存活和迁移的分子组分，并确定该途径是否促进体内神经嵴衍生肿瘤的转移。斑马鱼与人类基因组具有密切的同线性，其保守的分子途径调节组织和器官的发育，为进行此类研究提供了强有力的工具。该候选人已经鉴定并表征了具有特定神经嵴细胞存活和迁移缺陷的斑马鱼突变Foxd 3系，并鉴定了Snail B转录因子作为Foxd 3功能的关键介体。本申请的基本假设是，Foxd 3途径的知识将提供对神经嵴细胞如何在外来环境中迁移和存活的理解，这是神经嵴源性肿瘤转移的要求。在目标1中，遗传上位性和生物化学将确定Foxd 3是否直接激活神经嵴细胞中的Snail B表达，以及Snail B是否通过分别抑制有希望的候选物puma和e-钙粘蛋白的表达来抑制细胞凋亡和细胞迁移。在目标2中，将通过微阵列分析来自Foxd 3突变体和野生型同胞的GFP标记的神经嵴细胞，以鉴定和分析Foxd 3介导的神经嵴细胞存活和迁移的其他下游靶标。在目标3中，Foxd 3和snail B将在发育中的神经嵴细胞中过表达，以检查它们在建立的斑马鱼神经嵴肿瘤模型中促进转移的潜在作用。在正常发育过程中，神经管细胞脱离，激活生存程序并迁移到胚胎的远处区域。这一过程类似于人类癌症转移过程中细胞的行为方式。本申请的目标是找到参与正常胚胎存活和迁移程序的基因，并确定这些基因在癌症转移过程中是否异常激活。