Intercellular communication and competition between migrating cells

细胞间通讯和迁移细胞之间的竞争

• 批准号: 9083725
• 负责人: Gillian Stanfield
• 金额: $ 28.86万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-01 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9083725
• 关键词: Adhesions; Adult; Affect; Animals; Anthelmintics; Behavior; Biological Assay; Caenorhabditis elegans; Cells; Cellular Morphology; Data; Defect; Development; Disease; Embryonic Development; Employee Strikes; Environment; Fertility; Fertilization; Genes; Genetic Screening; Genetic study; Goals; Gonadal structure; Health; Histocompatibility Testing; Homeostasis; Human; Image; Imaging Device; Immigration; In Vitro; Individual; Inflammation; Life; Mediating; Modeling; Molecular; Movement; Nematoda; Oocytes; Organ; Outcome; Parasites; Pathway interactions; Pharmaceutical Preparations; Phosphotransferases; Plants; Process; Prostaglandins; Proteins; Regulation; Reproduction; Role; Signal Pathway; Signal Transduction; Sperm Count Procedure; Structure of primordial sex cell; Substrate Interaction; System; Testing; Tissues; cell behavior; cell motility; cell type; egg; extracellular; genetic makeup; genome editing; in vivo; insight; intercellular communication; male; migration; migratory population; mutant; public health relevance; repaired; reproductive tract; signal processing; sperm cell; success; time use; tool

 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.

 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，包括胚胎发生期间的器官形成、成体中的组织稳态和精子到卵子的旅程期间的有性生殖。该项目的目标是剖析细胞和分子机制，通过这些机制，单个迁移细胞感知其环境，通过改变其运动性做出反应，并在此过程中相互交流。我们正在利用一个高度易处理的系统来研究这些过程的遗传控制：线虫C的精子。优美的线虫精子通过爬行运动，类似于许多其他运动细胞类型，它们必须竞争以迁移和使卵母细胞受精。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靶组织的能力。自从C.线虫是小而透明的，迁移、竞争及其结果都可以在活体动物中直接观察到，并且存在许多工具来操纵迁移细胞及其周围环境的遗传组成。利用这些特征，我们开发了用于成像细胞行为的工具，并确定了在精子中起作用的激酶样蛋白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的内在和细胞的外在途径交叉控制迁移和竞争，并确定这些过程的其他监管机构。在目标1中，我们将确定COMP-1在调节细胞行为中的作用，这些行为对精子的迁移、定位和竞争都很重要。线虫和其他线虫。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，我们将继续进行成功的遗传筛选，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）揭示理解特定迁移行为如何影响迁移细胞在靶组织中的能力的一般范式，而不依赖于可能在组织类型之间变化的信号;（2）提供对前列腺素信号通路的直接洞察，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已知的重要性;以及（3）表征用于治疗线虫寄生虫害虫的驱虫药的候选靶标，所述线虫寄生虫害虫感染全世界沿着农业上重要的动物和植物的超过10亿个体，导致对人类健康和经济的巨大负担。