Regulation of Cell Migration in Development

发育过程中细胞迁移的调控

• 批准号: 7929984
• 负责人: Denise J. Montell
• 金额: $ 21.9万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7929984
• 关键词: Affect; Animals; Behavior; Biological Models; Cells; Collaborations; Complex; Computer Simulation; Cytokine Signaling; Development; Disease; Drosophila genus; Drug Delivery Systems; Embryonic Development; Epithelial; Epithelium; Feedback; Female; Fertility; Funding; Genes; Genetic; Genetic Screening; Growth Factor; Healed; Health; Human; Image; Individual; Laboratories; Lead; Learning; Life; Modeling; Molecular; Molecular Genetics; Morphology; Movement; Neoplasm Metastasis; Oocytes; Ovary; Pathway interactions; Phenotype; Play; Process; Property; Proteins; Regulation; Research; Role; Sampling; Signal Pathway; Signal Transduction; Study models; Techniques; Testing; Time; To specify; Work; Wound Healing; cancer cell; cell motility; cell type; cytokine; driving force; egg; fly; healing; in vivo; inhibitor/antagonist; mathematical model; migration; migratory population; monolayer; movie; mutant; public health relevance; receptor; steroid hormone; tumor

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 whether, when, and where cells move is significant for human health and disease. My laboratory has developed a relatively simple and genetically tractable model for the study of the developmental regulation of cell motility, the movement of a small group of cells in the Drosophila ovary known as the border cells. We have identified steroid hormone, cytokine and growth factor signaling pathways that are required for the spatial and temporal regulation of border cell migration. In the previous funding period we showed that integration of steroid hormone and cytokine signaling governs the developmental timing of border cell migration. We found that continuous signaling through the JAK/STAT pathway is required not only to specify the migratory population initially, but also to sustain motility throughout their migration. We made a significant advance by succeeding for the first time in time-lapse, live- imaging of border cell migration. Live-imaging has revealed several phenomena that were not evident in fixed samples, including that the process of detachment from the epithelium is long, slow and likely complex at the molecular level. For the cells to detach, we find that a sharp cell fate distinction must be made between cells that will migrate and those that will not. In a genetic screen for mutants that affect border cell development and migration, we identified the gene apontic as playing a critical role in this distinction. We further discovered that Apontic functions as a feedback inhibitor of JAK/STAT signaling that limits the migratory population, a process for which we developed a mathematical model and computer simulations that faithfully reproduce wild-type and mutant conditions. In our first specific aim we propose to test specific predictions of our model for Apt function and its interactions with SLBO and STAT. In aims 2 and 3, we propose to investigate the molecular mechanisms underlying the processes of detachment and directional guidance, respectively. Together these studies should significantly advance our understanding of the mechanisms that control collective cell movements, which we propose differ significantly from those controlling individual cells. 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 fruit fly, 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.

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，了解控制细胞是否、何时和何处移动的分子机制对人类健康和疾病具有重要意义。我的实验室开发了一个相对简单和遗传上易于处理的模型，用于研究细胞运动的发育调节，即果蝇卵巢中一小群细胞（称为边界细胞）的运动。我们已经确定了类固醇激素，细胞因子和生长因子的信号通路，所需的空间和时间调节边界细胞迁移。在之前的资助期间，我们发现类固醇激素和细胞因子信号传导的整合控制了边缘细胞迁移的发育时间。我们发现，通过JAK/STAT通路的持续信号不仅需要指定最初的迁移人口，而且还需要在整个迁移过程中维持运动性。我们取得了重大进展，首次成功地在定时，实时成像的边界细胞迁移。活体成像揭示了几种在固定样本中不明显的现象，包括从上皮细胞脱离的过程是漫长、缓慢的，并且在分子水平上可能是复杂的。为了使细胞分离，我们发现必须在迁移的细胞和不迁移的细胞之间进行明显的细胞命运区分。在影响边缘细胞发育和迁移的突变体的遗传筛选中，我们确定了基因apontic在这种区别中起着关键作用。我们进一步发现Apontic作为JAK/STAT信号传导的反馈抑制剂发挥作用，限制了迁移人口，我们开发了一个数学模型和计算机模拟，忠实地再现了野生型和突变体条件。在我们的第一个具体目标中，我们建议测试我们的模型对Apt功能及其与SLBO和STAT的相互作用的具体预测。在目标2和3中，我们分别提出了研究分离和定向引导过程的分子机制。总之，这些研究应该大大提高我们对控制集体细胞运动的机制的理解，我们认为这些机制与控制单个细胞的机制有很大不同。公共卫生关系：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。