Intercellular communication and competition between migrating cells

 描述(申请人提供)：迁移是一种基本的细胞行为，对许多过程至关重要，包括胚胎发育过程中的器官形成，成人的组织动态平衡，以及精子到卵子的旅程中的有性繁殖。这个项目的目标是剖析单个迁移细胞感知环境、通过改变它们的运动性来做出反应以及在这样做的过程中相互交流的细胞和分子机制。我们正在利用一种高度易处理的系统来研究这些过程的遗传控制：线虫的精子。线虫精子通过爬行移动，类似于许多其他可移动的细胞类型，它们必须竞争才能迁移和受精卵母细胞。因此，这个系统提供了一个平台，不仅可以研究控制运动的机制，还可以研究迁移细胞之间的差异如何影响它们进入和占据靶组织的能力。由于线虫小而透明，迁徙、竞争及其结果都可以在活体动物体内直接观察到，并且存在许多工具来操纵迁徙细胞及其周围环境的基因构成。利用这些特征，我们开发了对细胞行为进行成像的工具，并确定了在精子中发挥作用的类似激酶的蛋白CoMP-1，以及底物组织中调节精子迁移和竞争能力的前列腺素信号通路。我们现在建议确定这些细胞内在和细胞外在途径是如何相交的，以控制迁移和竞争，并定义这些过程的额外调节因素。在目标1中，我们将确定在线虫和其他线虫中，comp-1在调节对精子迁移、定位和竞争至关重要的细胞行为中的作用。在目标2中，我们将确定精子-性腺信号通路和受精组织内精子-底物相互作用对调节精子迁移、定位和竞争的贡献。在目标3中，我们将继续进行成功的基因筛查，以确定精子迁移、定位和竞争的新调节因素。我们的研究将(1)揭示一般范式，以了解特定的迁移行为如何影响迁移细胞填充目标组织的能力，独立于不同组织类型的信号；(2)提供对前列腺素信号通路的直接洞察，已知的前列腺素信号通路通过在炎症、生育和其他过程中的作用对人类健康和疾病具有重要作用；以及(3)描述驱虫药治疗线虫寄生虫害虫的候选靶标，线虫寄生虫与农业上重要的动植物一起感染全球超过10亿人，给人类健康和经济造成巨大负担。

 DESCRIPTION (provided by applicant): Migration is a fundamental cellular behavior that is critical for numerous processes including organ formation during embryogenesis, tissue homeostasis in the adult, and sexual reproduction during the journey of sperm to egg. The goal of this project is to dissect the cellular and molecular mechanisms by which individual migrating cells sense their environment, respond by altering their motility, and communicate with one another as they do so. We are taking advantage of a highly tractable system for studying the genetic control of these processes: sperm of the nematode C. elegans. Nematode sperm move by crawling, similar to many other motile cell types, and they must compete in order to migrate and fertilize oocytes. This system thus provides a platform to study not only the mechanisms that control motility, but also how differences between migrating cells affect their ability to entr and occupy a target tissue. Since C. elegans is small and transparent, migration, competition, and its outcome can all be directly observed within living animals, and many tools exist for manipulating the genetic makeup of migratory cells and their surroundings. Utilizing these features, we have developed tools for imaging cell behaviors and identified both a kinase-like protein, COMP-1, that functions in sperm, as well as a prostaglandin signaling pathway in substrate tissue that regulate the ability of sperm to migrate and compete. We now propose to determine how these cell-intrinsic and cell-extrinsic pathways intersect to control migration and competition and to define additional regulators of these processes. In Aim 1, we will determine the role of COMP-1 in regulating cell behaviors important for sperm migration, localization and competition, both in C. elegans and other nematodes. In Aim 2, we will identify the contribution of sperm-gonadal signaling pathways and sperm-substrate interactions within recipient tissues to regulating sperm migration, localization, and competition. In Aim 3, we will continue a successful genetic screen to identify new regulators of sperm migration, localization, and competition. Our studies will (1) reveal general paradigms for understanding how specific migratory behaviors affect the ability of migrating cells to populate a target tissue, independent of signals that may vary among tissue types; (2) provide direct insight into prostaglandin signaling pathways, which are of known importance for human health and disease through roles in inflammation, fertility, and other processes; and (3) characterize a candidate target for anthelmintic drugs to treat nematode parasites pests, which infect upward of 1 billion individuals worldwide along with agriculturally important animals and plants, resulting in immense burdens on human health and economies.