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Mechanism of Xenopus Cranial Neural Crest Cell Migration

非洲爪蟾颅神经嵴细胞迁移机制

基本信息

批准号：
7575150
负责人：
DOMINIQUE R ALFANDARI
金额：
$ 32.8万
依托单位：
UNIVERSITY OF MASSACHUSETTS AMHERST
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-03-01 至 2011-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7575150
关键词：
Anterior Antisense Oligonucleotides Asthma Cell Adhesion Cell Death Cell Proliferation Cell surface Cells Cephalic Cleaved cell Data Development Diagnosis Disintegrins Dominant-Negative Mutation Drug usage Embryo Embryonic Development Environment Epidermis Event Extracellular Matrix Face Fibronectins Histone H3 Human Immigration In Situ Hybridization In Situ Nick-End Labeling In Vitro Injection of therapeutic agent Jaw Label Lateral Lead Light Link Measures Mesoderm Messenger RNA Metalloproteases Modeling Neoplasm Metastasis Neural Crest Neural Crest Cell Oligonucleotides Pathway interactions Peptide Hydrolases Peripheral Nervous System Phenotype Phosphorylation Positioning Attribute Proteins Relative (related person)Research Personnel Signal Transduction Site Structure Testing Tissues Translations Work Xenopus adhesion receptor base cell motility craniofacial in vitro testing in vivo inhibitor/antagonist migration neural plate novel overexpression prevent programs protein function research study tumor

项目摘要

Proper cranial neural crest (CNC) cell migration is essential for the construction of the face, jaws and their peripheral nervous system connections. Despite this importance, little is known about how neural crest cell migration is regulated. During Xenopus embryo development the expression of ADAM13 (a protein containing A Disintegrin And Metalloprotease) correlates with the migration of the cranial neural crest cells from the lateral border of the neural plate to the ventral anterior station where they eventually form facial structures (Alfandari et al.,1997). Our on-going analyses of cranial neural crest cells expressing a dominant negative form of ADAM13 suggest that ADAM13 promotes and/or directs their migration in two of the three possible pathways. Our working hypothesis is that ADAM13 cleaves a protein that normally restricts cranial neural crest cell migration. This protein may either be inserted in the migration path as a stop signal to prevent cell passage or be expressed at the cranial neural crest cell surface to hold the cells in place as an anchor. To test these hypotheses and analyze whether other ADAM and related metalloproteases may also be involved in cranial neural crest cell migration we propose the following specific Aims. This proposal has three Aims to understand 1) if cells missing ADAM13 protein can use other ADAM and related metalloprotease to migrate, 2) if ADAM13 functions as a "drill" to open migration pathways, 3) if ADAM13 cuts an anchor that attaches cranial neural crest cells to their environment. Using specific morpholino oligonucleotides, we can prevent translation of ADAM proteins including ADAM13 in embryos and test how cranial neural crest cells migrate. This can be compared to the migration of cells in which ADAM13 function is blocked (using drug inhibitor). Using grafts we will test whether cranial neural crest cells missing ADAM13 activity can follow cells that have ADAM13. Finally, we will test if ADAM13 can cleave proteins that are known to anchor cells down. The proposed studies will increase our understanding of events that govern normal formation of the face, an essential step towards diagnosing and treating conditions that lead to abnormal development. Furthermore, information about ADAM contributions to cell migration could lead to new understanding of the function of these proteins in various cancer and metastasis. In particular these protein (ADAM) are likely to be involved in the escape of cells from the original tumor to new sites.

适当的颅神经嵴（CNC）细胞迁移对于面部、颌骨及其周围组织的构建至关重要。周围神经系统连接尽管如此重要，但人们对神经嵴细胞如何移民受到管制。在非洲爪蟾胚胎发育过程中，含有去整合素和金属蛋白酶）与颅神经嵴细胞的迁移相关从神经板的外侧边缘到腹前站，在那里它们最终形成面部结构（Alfandari等人，1997年）。我们正在进行的颅神经嵴细胞的分析， ADAM 13的阴性形式表明，ADAM 13促进和/或指导它们在三种中的两种中的迁移。可能的路径。我们的工作假设是，ADAM 13切割一种蛋白质，通常限制颅神经嵴细胞迁移这种蛋白质可以作为停止信号插入迁移路径中，阻止细胞通过或在颅神经嵴细胞表面表达，以将细胞保持在适当位置，锚。为了验证这些假设，并分析其他ADAM和相关金属蛋白酶是否也可能参与颅神经嵴细胞迁移，我们提出以下具体目的。这一建议三个目的了解1）如果细胞缺失ADAM 13蛋白，可以使用其他ADAM和相关金属蛋白酶迁移，2）如果ADAM 13作为“钻”打开迁移途径，3）如果ADAM 13 切断了一个将颅神经嵴细胞与周围环境相连的锚。使用特定的吗啉代寡核苷酸，我们可以阻止胚胎中包括ADAM 13在内的ADAM蛋白的翻译，并测试如何颅神经嵴细胞迁移。这可以与其中ADAM 13起作用的细胞的迁移相比较被阻断（使用药物抑制剂）。使用移植物，我们将测试缺失ADAM 13的颅神经嵴细胞是否活动可以跟随具有ADAM 13的细胞。最后，我们将测试ADAM 13是否可以切割蛋白质，已知它能将细胞锚下来。拟议中的研究将增加我们对统治事件的理解，面部的正常形成，这是诊断和治疗导致异常发育此外，关于ADAM对细胞迁移的贡献的信息可能导致这些蛋白质在各种癌症和转移中的功能的新认识。特别是这些蛋白（ADAM）可能参与细胞从原始肿瘤逃逸到新部位。