Regulation of Cohesive Cell Migration in Drosophila Embryogenesis

描述（由申请人提供）：细胞迁移对于胚胎发育、伤口愈合过程和病理状况（如肿瘤转移）至关重要。了解细胞以定向方式内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期间应用，以及在癌症进展期间如何出错。我们已经开发了一个简单的模型系统来研究粘性细胞迁移使用果蝇。在果蝇中，反向和正向遗传学方法与在完整生物体中真实的时间内研究细胞迁移的能力相结合，使我们能够识别参与这一过程的基因，并了解它们在细胞迁移中发挥的确切作用。由于人类和无脊椎生物之间的信号网络的保守性，这些研究的结果可以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个细胞在培养物中迁移的机制。我们目前的挑战是了解这些机制是否也适用于凝聚性细胞迁移，以及凝聚性细胞迁移与单细胞迁移的不同之处。在这里，我们专注于两个未回答的问题，有关粘性细胞迁移; 1）迁移的上皮细胞的粘附基质是如何协调与细胞间的细胞粘附和2）极性是如何产生的迁移集群内的净定向迁移。我们的第一个具体目标是测试的假设，整合素介导的粘附迁移上皮细胞和中胚层细胞，他们迁移引导上皮细胞的初始迁移路径，通过激活小GTdR Rac。我们的第二个目的是测试的假设，即Rac介导迁移的推进前和收缩的后方的上皮。在我们的第三和第四个目标，我们将确定和表征两个新的基因，确定在正向遗传学筛选整合素介导的粘附在粘性细胞迁移的作用。细胞迁移对于胚胎发育、创伤愈合和肿瘤转移是必不可少的。我们建议研究细胞如何在胚胎中迁移，以便我们可以应用我们的知识来设计治疗方法，以加速或延迟伤口愈合，并防止癌细胞的迁移和入侵。

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.