Mechanisms of Cell Competition in Growth and Development

生长发育中的细胞竞争机制

• 批准号: 9903400
• 负责人: Laura A Johnston
• 金额: $ 40.04万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9903400
• 关键词: Address; Animals; Biological Models; Cell Communication; Cell physiology; Cells; Communication; Competitive Behavior; Defect; Development; Drosophila genus; Genetic; Goals; Growth; Growth and Development function; Health; Innate Immune Response; Mediating; Molecular; Mosaicism; Normal tissue morphology; Pathway interactions; Physiology; Process; Proto-Oncogene Proteins c-myc; Ribosomal Proteins; Role; Signal Pathway; Signal Transduction; Tissues; Wing; Work; fitness; novel; novel strategies; prevent

The central problem this work addresses is how cells communicate their fitness and recognize aberrant fitness differences that might endanger growing tissues. Much evidence indicates that the recognition of fitness disparities elicits interactions that prevent the weaker cells from contributing to the animal, promoting optimal tissue and organismal fitness. Cell competition is a mechanism that facilitates this homeostatic process, and is initiated upon recognition of cells perceived as less fit by their more robust neighbors. Examples of competitive behavior between cells of different fitness are numerous, but the best studied those induced by reduced ribosomal proteins (Rp), or reduced or enhanced expression of the transcription factor Myc. The developing Drosophila wing is the critical paradigm for study of cell competition - as a model system it is unsurpassed for mosaic studies of cell-cell interactions in living animals, and offers unparalleled genetic and molecular toolkits. We recently discovered that communication between the “winner” and “loser” cells is mediated by a novel signaling pathway consisting of components co-opted from the highly conserved innate immune response pathways. Our long-term goal is to explore both proximate (how does this work) and ultimate (what is it for) questions about cell competition. In this proposal, we focus on three major quests: 1), to further explore the mechanism by which signal activation is controlled and restricted to only nearby “loser” cells; 2) to delineate the endogenous role of cell competition during normal animal physiology; and 3) to investigate the existence of a general mechanism of cell fitness sensing. !

这项工作解决的中心问题是细胞如何传达它们的适应性和识别 可能危及生长组织的异常适应性差异。许多证据表明， 对适应性差异的认识消除了阻止较弱细胞 有助于动物，促进最佳的组织和有机体的健康。细胞竞争是 促进这种自我平衡过程的机制，并在识别细胞后启动 被他们更强壮的邻居认为不太适合。竞争行为的例子 不同适合度的细胞很多，但研究得最好的是那些由还原核糖体诱导的细胞。 蛋白（Rp），或减少或增强的转录因子Myc的表达。发展中 果蝇翅膀是研究细胞竞争的关键范例-作为一个模型系统， 在活体动物细胞间相互作用的马赛克研究中无与伦比，并提供无与伦比的 基因和分子工具箱。我们最近发现，“赢家”和 而“失败者”细胞是由一种新的信号通路介导的， 来自高度保守的先天免疫反应途径。我们的长期目标是探索 关于细胞竞争的近端问题（这是如何工作的）和最终问题（它是为了什么）。 在这一建议中，我们重点关注三个主要问题：1）进一步探索机制， 信号激活被控制并仅限于附近的“失败者”小区; 2）描绘出 在正常动物生理过程中细胞竞争的内源性作用;以及3）研究 存在细胞适合度感测的一般机制。 !