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。我的实验室已经开发了一个相对简单和遗传上易于处理的模型，用于研究细胞迁移，即果蝇卵巢中被称为边界细胞的一小群细胞的移动。在之前的资助期间，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，成功地对迁移的边界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细胞迁移领域的一个主要未解决的问题：如何整合细胞极性和细胞骨架动力学来实现一组细胞的协调，定向迁移。为了解决这个普遍的问题，我们将结合遗传方法，实时成像和生物化学的两个具体目标。首先是验证我们命名为FAV的一种蛋白质及其哺乳动物同源物的假设，它可以放大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结合起来。第二个目的是验证新发现的蛋白质Tiarin及其人类同源物是肌动蛋白动力学和细胞运动的保守调节因子的假设。总之，这些研究将为控制边界细胞迁移的机制提供见解，将这些发现与肌动蛋白动力学的更广泛领域联系起来，并使用该模型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：移动能力是几乎所有动物细胞的特性，从苍蝇和蠕虫等简单动物一直到人类。这项研究的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它们在何时、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.