Influence of tissue architecture on STAT-mediated morphogenesis and cell migration

在动物发育过程中，细胞扮演不同的角色，并适当地排列自己，形成组织和整个有机体。 如果这些过程失败，发育中的有机体可能有出生缺陷或可能死亡。关于指示细胞承担某些角色或迁移到所需位置的分子信号，我们已经知道很多，但细胞存在于复杂的环境中，并且尚不清楚组织的物理排列如何影响细胞之间的信号传递。首席研究员的研究小组最近的研究表明，细胞之间的小间隙可能会显着影响信号的扩散和细胞运动。 该项目的目标是表征组织形状对细胞信号传导和器官发育的影响。 研究人员将联合收割机结合遗传学、活体组织信号观察和计算机建模。通过这项工作确定的信号机制应该在动物的发育中发挥类似的作用。 因此，该项目将推进我们对基本生物机制的认识;特别是，控制发育的生物物理因素，包括模式形成，细胞的联合运动和细胞间信号的调节。PI将把这项研究与她在改善生物学高等教育方面的持续努力相结合。 她将培养批判性思维和跨学科研究方法的本科生和研究生，通过与现有项目合作，扩大代表性不足的个人在科学领域的参与，并参与社区外展工作。为了确定组织结构如何影响形态发生，研究小组专门研究了果蝇的卵巢。 研究果蝇已被证明是发现在包括人类在内的许多生物体中发挥作用的新基因和信号机制的有力策略。在卵巢中，上皮来源的边缘细胞在Janus激酶/信号转导和转录激活因子（Jak/STAT）途径激活后变得能动。在卵子发生过程中，一种可扩散的激活剂从两个卵泡细胞中释放出来，并以剂量依赖性的方式在附近的细胞中开启STAT信号传导。 活化的细胞集体向高水平分泌的化学引诱物迁移。先前的工作表明，这些信号事件是由保守的机制。该项目利用了果蝇遗传学、数学建模和发育中卵子相对简单的结构，可以实时成像以观察体内相互作用的细胞类型。具体而言，研究人员将：1）研究可扩散分泌信号的动态如何调节，以及组织结构内的间隙如何塑造其信号转导梯度和由此产生的细胞规格，以及2）确定边界细胞迁移的微环境中的细胞景观如何影响集体细胞迁移行为和分泌指导线索的局部浓度。 总的来说，该项目将整合尖端的跨学科研究，为下一代潜在的科学家提供出色的教育机会。

Nontechnical paragraph:During animal development, cells take on different roles and arrange themselves properly to form tissues and the whole organism. If these processes fail, the developing organism could have birth defects or may die. Much is known about the molecular signals that instruct cells to adopt certain roles or migrate to required places, but cells exist in complex environments, and it is not clear how the physical arrangement of tissues affects cell signaling to each other. Recent studies from the Principal Investigator's research group suggest that small gaps between cells may significantly affect both the diffusion of signals and cell movements. The goal of this project is to characterize the effect of tissue shape on cell signaling and organ development. The researchers will combine genetics, observation of signals in living tissues, and computer modeling. The signal mechanisms identified through this work should function similarly in the development of animals generally. Thus, this project will advance our knowledge of fundamental biological mechanisms; in particular, the biophysical factors that govern development, including pattern formation, joint movements of cells, and regulation of cell-cell signals. The PI will integrate this research with her continued efforts in improving higher education in biology. She will train undergraduate and graduate students in critical thinking and interdisciplinary research methods, expand participation of underrepresented individuals in science by partnering with existing programs, and engage in community outreach efforts. Technical paragraph:To determine how tissue structure influences morphogenesis, the research team specifically investigates the Drosophila ovary. Studying Drosophila has proven to be a powerful strategy to discover new genes and signaling mechanisms that function in many organisms, including humans. In the ovary, the epithelial-derived border cells become motile upon activation of the Janus Kinase/Signal Transducer and Activator of Transcription (Jak/STAT) pathway. During oogenesis, a diffusible activator is released from two follicle cells and functions to turn on STAT signaling in a dose-dependent fashion in nearby cells. Activated cells migrate collectively toward high levels of secreted chemoattractants. Prior work suggests that these signaling events are regulated by conserved mechanisms. The project takes advantage of Drosophila genetics, mathematical modeling, and the relatively simple architecture of the developing egg, which can be imaged live to observe cell types interacting in vivo. Specifically, the researchers will: 1) investigate how the dynamics of a diffusible secreted signal are regulated, and how gaps within tissue architecture shape its signal transduction gradient and resultant cell specification, and 2) determine how the landscape of cells in the microenvironment through which the border cells migrate affects collective cell migration behaviors and local concentrations of secreted guidance cues. Overall, this project will integrate cutting-edge, interdisciplinary research with outstanding educational opportunities for the next generation of potential scientists.