Intercellular communication and competition between migrating cells

 描述（由申请人提供）：迁移是一种基本的细胞行为，对许多过程至关重要，包括胚胎发生过程中的器官形成、成人的组织稳态以及精子到卵子过程中的有性生殖。该项目的目标是剖析单个迁移细胞感知环境、通过改变其运动性做出反应以及在这样做时相互交流的细胞和分子机制。我们正在利用一个高度易于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，类似于许多其他运动细胞类型，它们必须竞争才能迁移并使卵母细胞受精。因此，该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目标组织的能力。由于秀丽隐杆线虫体积小且透明，因此迁移、竞争及其结果都可以在活体动物体内直接观察到，并且存在许多用于操纵迁移细胞及其周围环境的基因组成的工具。利用这些特征，我们开发了细胞行为成像工具，并鉴定了在精子中发挥作用的类激酶蛋白 COMP-1，以及基质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如何交叉以控制迁移和竞争，并定义这些过程的额外调节因子。在目标 1 中，我们将确定 COMP-1 在调节细胞行为中的作用，这对秀丽隐杆线虫和其他线虫中的精子迁移、定位和竞争很重要。在目标 2 中，我们将确定受体组织内精子-性腺信号通路和精子-基质相互作用对调节精子迁移、定位和竞争的贡献。在目标 3 中，我们将继续成功的基因筛选，以确定精子迁移、定位和竞争的新调节因子。我们的研究将（1）揭示一般范例，用于理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，而与组织类型之间可能不同的信号无关； (2) 提供对前列腺素信号通路的直接了解，已知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意义； (3) 确定驱虫药物的候选靶点，用于治疗线虫寄生虫害虫，线虫寄生虫感染全世界超过 10 亿人以及农业上重要的动植物，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.