Mechanisms of cell competition that regulate growth during development

描述（由申请人提供）：后生动物组织是细胞群的复杂集合，它们的增殖能力通常不同。在组织扩张过程中，细胞是如何交流它们的生长状态的，无论是发育的还是稳态的，很大程度上是未知的。这个基本问题对医学和健康的许多方面都很重要，包括器官再生和移植；干细胞生物学和癌症。在以前的工作中，我们得到的结果表明，细胞通过局部细胞-细胞信号传导来测量它们的生长和代谢潜力。其他研究结果表明，在信号交换过程中，细胞代谢在每个细胞群中都发生了改变。第三，研究结果表明p53在细胞代谢变化中起关键作用。我们建议在果蝇身上进行实验，以这些结果为基础，利用其强大的遗传和分子工具。我们将使用基因组分析、突变体遗传分析、体细胞克隆技术以及体外和体内生化和分子分析来实现三个具体目标：继续发现和功能验证细胞竞争过程中重要的基因和信号通路，确定竞争性CM中导致失败者细胞死亡和赢家细胞增殖的活性因子，并确定p53及其靶标在竞争过程中感知和调节代谢变化中的作用。这些研究将揭示上皮细胞之间相互作用的潜在机制，这可能对改善人类的健康和护理有价值。此外，它们将扩展我们对生长过程中细胞-细胞通讯的基本方面的理解。

DESCRIPTION (provided by applicant): Metazoan tissues are complex assemblies of cell populations that often differ in their ability to proliferate. How cells communicate their growth status during tissue expansion, be it developmental or homeostatic, is largely unknown. This fundamental question is important to many aspects of medicine and health, including organ regeneration and transplantation; stem cell biology, and cancer. In previous work we obtained results suggesting that cells measure their growth and metabolic potential through local cell-cell signaling. Additional findings indicated that cellular metabolism is altered in each cell population during the signaling exchange. Third, results were obtained that showed that p53 plays a key role in the cellular metabolic changes. We propose experiments to build upon these results in Drosophila, to take advantage of its powerful genetic and molecular tools. We will use genomic profiling, genetic analysis of mutants, somatic cloned techniques, and in vitro and in vivo biochemical and molecular analysis to achieve three specific aims: To continue to uncover and functionally validate genes and signaling pathways that are important during cell competition, to identify the active factors in competitive CM that lead to death of loser cells and proliferation of winner cells, and to determine the role of p53 and its targets in sensing and regulating metabolic changes during competition. These studies will reveal mechanisms underlying interactions between cells in growing epithelia that may be valuable for improving the health and care of humans. In addition, they will expand our understanding of fundamental aspects of cell-cell communication during growth.