Mechanisms of Cell Competition in Growth and Development

生长发育中的细胞竞争机制

• 批准号: 10378546
• 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/10378546
• 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. !

这项工作解决的核心问题是细胞如何传达它们的适应性并识别 异常的健康差异可能会危及正在生长的组织。大量证据表明 对适应度差异的认识会引发相互作用，从而防止较弱的细胞 对动物做出贡献，促进最佳组织和机体健康。细胞竞争是 促进这种稳态过程的机制，并在细胞识别后启动 被更强大的邻居认为不太适合。之间竞争行为的例子 不同适应性的细胞有很多，但对那些由核糖体减少诱导的细胞进行了最好的研究 蛋白 (Rp)，或转录因子 Myc 的表达减少或增强。发展中的 果蝇翅膀是细胞竞争研究的关键范例——作为一个模型系统，它是 在活体动物细胞间相互作用的镶嵌研究方面无与伦比，并提供无与伦比的 遗传和分子工具包。我们最近发现，“胜利者”之间的沟通 “失败者”细胞是由一种新的信号通路介导的，该信号通路由增选的成分组成 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 关于细胞竞争的直接问题（它是如何工作的）和最终问题（它的用途是什么）。 在这个建议中，我们重点关注三个主要任务：1）进一步探索机制 信号激活受到控制并仅限于附近的“失败者”细胞； 2) 划定 正常动物生理过程中细胞竞争的内源性作用； 3) 调查 细胞适应性感知的一般机制的存在。 ！