Mechanisms of cell competition that regulate growth during development

发育过程中调节生长的细胞竞争机制

• 批准号: 7131768
• 负责人: Laura A Johnston
• 金额: $ 28.64万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7131768
• 关键词: Drosophilidae; RNA interference; biological signal transduction; cell growth regulation; cell population study; cell proliferation; developmental genetics; functional /structural genomics; gene expression; gene expression profiling; genetic regulation; genetic screening; imaginal disc; microarray technology; mixed tissue /cell culture; transcription factor

DESCRIPTION (provided by applicant): The overall goal of this proposal is to identify the molecular mechanisms underlying cell competition, in which normally viable cells are eliminated via apoptosis when they grow next to cells with higher growth rates. During cell competition, the loss of the "loser" cells is compensated by extra proliferation of the "winners", thus the organ develops to a normal size with appropriate cell fates. Our previous work demonstrated that cells with different expression levels of the c-myc proto-oncogene ortholog dMyc compete with each other, and that this competition has a critical role in regulating Drosophila wing size. What makes some cells "winners" of the competition and other cells "losers"? Based on our previous work, we hypothesize that dMyc-induced cell competition is mediated by a short-range signal that leads to specific genetic programs in both the "winners" and the "losers". With this in mind, we propose a systematic approach to identify the molecular mechanisms underlying cell competition. Using both an in vivo wing disc model system and a cell-culture based cell competition assay, the experiments we propose here will address how "winner" and "loser" cells are determined, and how information about their status is communicated between the cell populations. Our primary objectives are to determine the gene expression differences between competing cell populations and obtain a genetic signature of cell competition, to identify genes that are required for cell competition to occur, and to address the function of these genes in the competitive process. Since cell competition has also been documented in the mouse, the mechanism of cell competition as well as its role in development is likely conserved between flies and vertebrates. Furthermore, Myc expression is increased in many cancers, thus such a mechanism could also be used by incipient tumors to kill off nearby normal cells and expand their territory. We postulate that cell competition in Drosophila may provide a unique model with which genes that are involved in the earliest steps of cancer progression can be identified.

描述（由申请人提供）：该提案的总体目标是确定细胞竞争基础的分子机制，在这种细胞竞争竞争中，通常通过凋亡消除了通常可以通过凋亡的细胞生长在具有较高生长速率的细胞旁边的细胞。在细胞竞争期间，“失败者”细胞的损失是通过“获胜者”的额外增殖来补偿的，因此器官会在适当的细胞命运下形成正常大小。我们以前的工作表明，具有不同表达水平的C-MYC原始癌基因直媒DMYC相互竞争，并且该竞争在调节果蝇翼大小中具有关键作用。是什么使某些细胞“竞争”和其他细胞“失败者”？根据我们以前的工作，我们假设DMYC诱导的细胞竞争是由一个短距离信号介导的，该信号导致“获奖者”和“失败者”中的特定遗传程序。考虑到这一点，我们提出了一种系统的方法来识别细胞竞争的分子机制。使用体内机翼模型系统和基于细胞培养的细胞竞争测定法，我们在这里提出的实验将解决如何确定“赢家”和“失败者”细胞，以及如何在细胞种群之间传达有关其状态的信息。我们的主要目标是确定竞争细胞群体之间的基因表达差异，并获得细胞竞争的遗传特征，以识别发生细胞竞争所需的基因，并解决这些基因在竞争过程中的功能。由于细胞竞争也已在小鼠中记录在小鼠中，因此细胞竞争的机理及其在发育中的作用很可能在苍蝇和脊椎动物之间保存。此外，许多癌症在许多癌症中的表达增加，因此，初期肿瘤也可以使用这种机制来杀死附近的正常细胞并扩大其领域。我们假设果蝇中的细胞竞争可能会提供一个独特的模型，可以鉴定出与癌症进展最早步骤相关的基因。