Cytoskeleton Dynamics in Developmental Cell Migration

描述（由申请人提供）：细胞迁移是胚胎发育、伤口愈合和肿瘤转移的主要驱动力。因此，了解控制细胞运动的分子机制对人类健康具有重要意义。我的实验室开发了一个相对简单和遗传学上易于处理的模型，用于研究细胞迁移，即果蝇卵巢中一小群细胞（称为边界细胞）的运动。在上一个资助期，我们已经确定并表征了一些新的边界细胞迁移基因。我们还克服了一个主要的技术障碍，成功地对迁移的边缘细胞进行了延时实时成像。我们建议在这些进展的基础上，解决一个主要的未解决的问题，在细胞迁移领域：如何整合细胞极性和细胞骨架动力学，以实现协调，定向迁移的一组细胞。为了解决这个普遍的问题，我们将结合联合收割机的遗传方法，活成像和生物化学与两个具体的目标。第一个是测试我们命名为FAV的蛋白质及其哺乳动物同源物的假设，放大EGFR依赖的细胞极性，并将EGFR信号传导，运输和细胞极性与肌动蛋白动力学整合在一起。第二个目的是测试假设，一个新发现的蛋白质，Tiarin，和它的人类同源物，是保守的调节肌动蛋白动力学和细胞运动。这些研究将共同提供控制边界细胞迁移的机制的见解，将研究结果与更广泛的肌动蛋白动力学领域相关联，并使用该模型来识别和表征对人类健康和疾病重要的基因。公共卫生相关性：运动能力是几乎所有动物细胞的一种特性，从简单的动物如苍蝇和蠕虫，一直到人类。拟议的研究重点是果蝇中一小群细胞的运动，以了解更多关于特定分子如何协调何时，何地以及如何移动的信息。由于细胞运动有助于伤口愈合和肿瘤转移，这些研究可能导致发现新的药物靶点，可以促进愈合或抑制癌细胞的扩散。

DESCRIPTION (provided by applicant): Cell migration is a major driving force in embryonic development, wound healing, and tumor metastasis. Therefore, understanding the molecular mechanisms that control cell motility is significant for human health. My laboratory has developed a relatively simple and genetically tractable model for the study of cell migration, the movement of a small group of cells in the Drosophila ovary known as the border cells. In the previous funding period we have identified and characterized a number of new border cell migration genes. We also overcame a major technical obstacle and succeeded in time-lapse, live-imaging of migrating border cells. We propose to build upon these advances to address a major unsolved question in the field of cell migration: how cell polarity and cytoskeletal dynamics are integrated to achieve coordinated, directed migration of a group of cells. To address this general question, we will combine genetic approaches, live-imaging and biochemistry with two specific aims. The first is to test the hypothesis that a protein we have named FAV, and its mammalian homologs, amplify EGFR-dependent cell polarity and integrate EGFR signaling, trafficking and cell polarity with actin dynamics. The second aim is to test the hypothesis that a newly identified protein, Tiarin, and its human homolog, are conserved regulators of actin dynamics and cell motility. Together these studies will provide insights into the mechanisms controlling border cell migration, correlate the findings with the broader field of actin dynamics, and use this model to identify and characterize genes important in human health and disease. PUBLIC HEALTH RELEVANCE: The ability to move is a property of cells from virtually all animals, from simple ones such as flies and worms, all the way to humans. The proposed research focuses on the movement of a small group of cells in the fruitfly, to learn more about how specific molecules orchestrate when, where and how they move. Since cell motility contributes to wound healing and tumor metastasis, these studies could lead to the discovery of new drug targets that could promote healing or inhibit the spread of cancer cells.