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，了解控制细胞是否移动的分子机制对于人类健康和疾病是否重要。我的实验室开发了一个相对简单且遗传上的模型，用于研究细胞运动的发育调控，这是果蝇卵巢中一小部分细胞的运动，称为边界细胞。我们已经鉴定出类固醇激素，细胞因子和生长因子信号传导途径是边界细胞迁移的空间和时间调节所必需的。在上一个资金期间，我们表明类固醇激素和细胞因子信号的整合决定边界细胞迁移的发育时机。我们发现，不仅需要通过JAK/STAT途径进行连续信号传导，不仅要指定迁徙人群，而且还需要在整个迁移过程中维持运动能力。我们首次取得了延时，对边界细胞迁移的现场成像，取得了重大进步。现场成像揭示了几种在固定样品中不明显的现象，包括从上皮的脱离过程在分子水平上很长，缓慢且可能是复杂的。为了使细胞分离，我们发现必须在将迁移的细胞与不会迁移的细胞之间进行尖锐的细胞命运区别。在影响边界细胞发育和迁移的突变体的遗传筛选中，我们确定基因的根本性在这种区别中起着关键作用。我们进一步发现，泛质是限制迁移群体的JAK/Stat信号的反馈抑制剂，我们开发了一个数学模型和计算机模拟的过程，该过程忠实地重现了野生型和突变条件。在我们的第一个特定目的中，我们建议测试对APT功能的模型的特定预测及其与SLBO和STAT的相互作用。在目标2和3中，我们提出分别研究分离和定向引导过程的分子机制。这些研究总之应该显着提高我们对控制集体细胞运动的机制的理解，而我们建议的机制与控制单个细胞的机制有显着差异。公共卫生相关性：移动的能力是几乎所有动物的细胞的特性，从果蝇和蠕虫等简单的动物一直到人类。拟议的研究集中于果蝇中一小部分细胞的运动，以更多地了解特定分子如何在何时，何地和如何移动方面进行。由于细胞运动有助于伤口愈合和肿瘤转移，因此这些研究可能导致发现可以促进愈合或抑制癌细胞扩散的新药物靶标。