Physical and chemical cues synergistically direct collective cell migration

细胞迁移是包括人类在内的动物正常发育所必需的，并且对于包括免疫反应和伤口愈合在内的功能至关重要。这个过程是高度保守的，并由各种信号控制，这些信号指导细胞移动到正确的位置。然而，目前还不清楚这些来自细胞环境的线索如何在复杂和动态的组织中随着它们的发育而变化。已知迁移细胞在不同的环境中表现不同，但不知道这些细胞如何解释物理线索与化学线索，或者它们如何整合这些信息。该项目利用跨学科方法，结合了果蝇的细胞生物学和遗传学以及数学建模。这些系统将用于询问化学和物理线索如何结合以导致准确的细胞迁移。这项研究将与正在进行的战略努力相辅相成，以扩大和改善研究培训和生物学教育。这包括努力指导和培训本科生和研究生进行研究，分析和解释;扩大历史上代表性不足的个人在科学事业中的参与;加强本科生的定量推理技能，作为NSF改善本科生科学教育（IUSE）倡议的一部分，在大班;通过实施教学和辅导方面的最佳做法，改进高级课程和研究培训;与科学界外联方案合作。因此，该项目将促进我们对发育生物学的理解，同时为对科学感兴趣的人提供尖端教育和新的机会。该项目利用分子，遗传，成像和建模方法来研究细胞如何解释物理和化学信息的组合以正确迁移。目前尚不清楚细胞如何感知化学信号浓度的微小差异，以在化学引诱物梯度中定位自己，或者这种信号如何在组织生长和重塑时准确地起作用。此外，细胞如何机械地响应于它们沿着其移动的基底的物理特性还没有很好地建立。此外，物理结构对异质组织中化学信号分布的影响还没有得到很好的表征。在细胞簇一起移动的情况下，也不清楚它们在移动时如何相互传递空间信息。 这项工作将解决这些问题，通过一个集群的运动细胞，称为边界细胞，在生殖细胞之间迁移的反应受体酪氨酸激酶信号在果蝇卵子发生的表征。本研究旨在确定边缘细胞迁移行为的变化与它们在卵室中移动时遇到的各种物理结构之间的关系;确定卵室中活性化学引诱物的分布以及控制这种模式的物理和化学成分;并揭示了运动细胞簇内介导浓度依赖性迁移行为的指导受体信号传导的动力学。研究结果将为深入了解发育信号、定向细胞运动和体内细胞行为协调变化的一般机制提供帮助。该奖项反映了NSF的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

Cell migration is required for animals, including humans, to develop normally and is essential for functions including immune response and wound healing. This process is highly conserved and controlled by various signals that direct cells to move to the correct places. However, it is not understood how these cues from the cell’s environment are changed in complex and dynamic tissues as they develop. It is known that migratory cells behave differently in different contexts, but not known how those cells interpret physical cues versus chemical cues or how they integrate these sets of information. This project takes advantages of interdisciplinary approaches combining the well-characterized cell biology and genetics of fruit flies and mathematical modeling. These systems will be used to ask how chemical and physical cues are combined to result in accurate cell migration. This research will be complemented with ongoing, strategic efforts to broaden and improve research training and biology education. This includes efforts to mentor and train undergraduate and graduate students in research, analysis, and interpretation; expand participation of historically underrepresented individuals in scientific careers; strengthen the quantitative reasoning skills of undergraduates, as part of the NSF-Improving Undergraduate Science Education (IUSE) initiative, in large classes; improve upper-level courses and research training through implementation of best-practices in pedagogy and mentoring; and partner with scientific community outreach programs. Thus, the project will advance our understanding of developmental biology while providing cutting-edge education and new opportunities for people interested in science. This project utilizes molecular, genetic, imaging and modeling approaches to examine how cells interpret a combination of physical and chemical information to migrate correctly. It is not well understood how cells sense small differences in concentrations of chemical cues to orient themselves in a chemoattractant gradient, or how this signaling works accurately as tissues grow and remodel. In addition, how cells mechanistically respond to the physical characteristics of the substrates along which they move is not well established. Moreover, the impact that physical structure has on chemical cue distribution in a heterogenous tissue is not well characterized. In cases when clusters of cells move together, it is also unclear how they communicate spatial information to each other as they move. This work will address these questions through the characterization of a cluster of motile cells, called border cells, that migrate between germline cells in response to receptor tyrosine kinase signaling during Drosophila oogenesis. This research aims aim to identify the relationship between changes in the migratory behavior of border cells and the varied physical structures they encounter while moving through the egg chamber; determine the distribution of active chemoattractants in egg chambers and the physical and chemical components that govern this pattern; and uncover the dynamics of guidance receptor signaling within a motile cell cluster that mediate concentration-dependent migratory behaviors. The results will provide insight into general mechanisms of developmental signaling, directed cell motility, and coordinated changes of cell behaviors in vivo.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.