Mechanisms of cell competition that regulate growth during development

描述(申请人提供)：后生动物组织是细胞群体的复杂集合，它们的增殖能力往往不同。细胞在组织扩张过程中是如何传递其生长状态的，无论是发育的还是稳态的，在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，我们获得的结果表明，细胞通过局部细胞-细胞信号来衡量其生长和代谢潜力。其他发现表明，在信号交换过程中，每个细胞群的细胞代谢都发生了变化。第三，研究结果表明，P53在细胞代谢变化中起关键作用。我们建议在这些结果的基础上对果蝇进行实验，以利用其强大的遗传和分子工具。我们将利用基因组图谱、突变体的遗传分析、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特定目标：继续发现并从功能上验证在细胞竞争中重要的基因和信号通路；识别竞争性CM中导致失败者细胞死亡和获胜者细胞增殖的活跃因素；以及确定P53及其靶点在检测和调节竞争过程中代谢变化中的作用。这些研究将揭示生长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，它们还将扩大我们对生长过程中细胞间交流的基本方面的理解。

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.