Regulation of Cohesive Cell Migration in Drosophila Embryogenesis

果蝇胚胎发生中粘性细胞迁移的调控

基本信息

批准号：
8231506
负责人：
MONN MONN MYAT
金额：
$ 32.93万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
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：
2008-03-01 至 2014-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8231506
关键词：
Adhesions Biological Models Biological Process Cell Death Cell Proliferation Cell physiology Cell surface Cell-Cell Adhesion Cells Distal Down-Regulation Drosophila genus Drosophila melanogaster E-Cadherin Embryo Embryonic Development Epithelial Epithelial Cells Epithelium Event Family Filopodia Genes Genetic Genetic Screening Gland Goals Guanosine Triphosphate Phosphohydrolases Human Imaging Techniques Impaired wound healing Integrins Invertebrates Knowledge Learning Life Mammalian Cell Mediating Membrane Mesoderm Mesoderm Cell Modeling Monomeric GTP-Binding Proteins Neoplasm Metastasis Neurons Organ Organism Pathologic Processes Play Process Regulation Role Salivary Glands Signal Transduction System Testing Time Tissues Tumor Cell Invasion Visceral Wound Healing base cancer cell cell motility embryo cell genetic manipulation human migration insight migration novel prevent rho rho GTP-Binding Proteins therapy design tumor tumor progression

项目摘要

DESCRIPTION (provided by applicant): Cell migration is essential for embryonic development, wound healing processes and pathological conditions such as tumor metastasis. An understanding of the mechanism by which cells migrate cohesively in a directed manner will provide fundamental insights into the formation of tissues and organs and will help us understand how these mechanisms are applied during wound healing and go awry during cancer progression. We have developed a simple model system to study cohesive cell migration using the fruit fly Drosophila. In Drosophila, the combination of reverse and forward genetic approaches with the ability to study cell migration in an intact organism in real time allows us to identify genes involved in this process and understand the precise roles they play in cell migration. Due to the conservation of signaling networks between humans and invertebrate organisms, results of these studies can be applied to migration of human cells. Studies using cultured mammalian cells have revealed the mechanism by which single cells migrate in culture. Our current challenge is to understand whether such mechanisms also apply to cohesive cell migration and how cohesive cell migration differs from single cell migration. Here we focus on two unanswered questions concerning cohesive cell migration; 1) how adhesion of migrating epithelial cells to the substratum is coordinated with cell-cell adhesion between cells and 2) how polarity is generated within the migrating cluster for net directed migration. Our first specific aim is to test the hypothesis that integrin-mediated adhesion between the migrating epithelial cells and the mesodermal cells upon which they migrate guide the initial migratory path of the epithelia by activating the small GTPase Rac. Our second aim is to test the hypothesis that Rac mediates migration of the advancing front and contraction of the rear of the epithelium. In our third and fourth aims we will identify and characterize two novel genes identified in a forward genetics screen for their roles in integrin-mediated adhesion during cohesive cell migration. Cell migration is essential for embryonic development, wound healing and tumor metastasis. We propose to study how cells migrate cohesively in the embryo so that we can apply our knowledge to design therapies to expedite or delay wound healing and prevent migration and invasion of cancer cells.

描述（由申请人提供）：细胞迁移对于胚胎发育、伤口愈合过程和肿瘤转移等病理状况至关重要。了解细胞以定向方式凝聚迁移的机制将为组织和器官的形成提供基本见解，并将帮助我们了解这些机制如何在伤口愈合过程中应用以及在癌症进展过程中如何出错。我们开发了一个简单的模型系统来使用果蝇研究粘性细胞迁移。在果蝇中，反向和正向遗传方法与实时研究完整生物体中细胞迁移的能力相结合，使我们能够识别参与该过程的基因并了解它们在细胞迁移中发挥的精确作用。由于人类和无脊椎动物之间信号网络的保护，这些研究结果可应用于人类细胞的迁移。使用培养的哺乳动物细胞的研究揭示了单细胞在培养物中迁移的机制。我们当前的挑战是了解这种机制是否也适用于粘性细胞迁移以及粘性细胞迁移与单细胞迁移有何不同。在这里，我们重点关注有关粘性细胞迁移的两个尚未解答的问题； 1) 迁移上皮细胞与基质的粘附如何与细胞之间的细胞间粘附相协调，2) 迁移簇内如何产生极性以实现净定向迁移。我们的第一个具体目标是测试以下假设：整合素介导的迁移上皮细胞与其迁移的中胚层细胞之间的粘附通过激活小 GTPase Rac 来引导上皮细胞的初始迁移路径。我们的第二个目的是检验 Rac 介导上皮细胞前部迁移和后部收缩的假设。在我们的第三个和第四个目标中，我们将鉴定和表征在正向遗传学筛选中鉴定的两个新基因，了解它们在粘性细胞迁移过程中整合素介导的粘附中的作用。细胞迁移对于胚胎发育、伤口愈合和肿瘤转移至关重要。我们建议研究细胞如何在胚胎中粘附地迁移，以便我们可以应用我们的知识来设计疗法，以加速或延迟伤口愈合并防止癌细胞的迁移和侵袭。