Cell Competition in Development and Homeostasis

描述(由申请人提供)：本项目的目标是阐明保护单个细胞遗传完整性的机制。DNA损伤导致单个细胞的基因数量改变在肿瘤中非常常见，并有助于肿瘤的进展。人们认为，随着时间的推移，身体中的许多细胞也会受到类似的损害。事实上，这种损害可能是衰老过程的一个标志，也是导致与年龄有关的疾病的一个因素，包括痴呆症、心血管疾病和糖尿病，以及癌症。通过使用含有不同基因类型细胞的果蝇嵌合体动物来模拟基因组变化，可以在实验中研究这种体细胞遗传多样性的影响。该项目检验了一种假说，即核糖体蛋白基因的不平衡会引发细胞竞争反应，从而使核糖体蛋白基因从有利于或其他基因正常的细胞中移除。除了众所周知的核糖体蛋白在蛋白质合成中的作用之外，负责这一额外功能的特定核糖体蛋白的结构域将通过对体内克隆基因的结构和功能分析来确定。将特别注意核糖体蛋白在细胞内的重要位置，以及核糖体蛋白失衡激活萨尔瓦多-河马-沃茨途径的肿瘤抑制因子以促进受损细胞消除的假设。将进行基因筛选，以确定这一过程的其他组成部分，并寻求确定核糖体蛋白失衡导致细胞消除的分子机制。

DESCRIPTION (provided by applicant): The goal of this project is to elucidate mechanisms that protect the genetic integrity of individual cells. DNA damage that leads altered gene numbers in individual cells is very common in tumors, and contributes to their progression. Similar damage is thought to occur in many cells in the body over time. Indeed such damage may be a hallmark of the aging process and a contributor to age related diseases including dementia, cardiovascular disease and diabetes, in addition to cancer. By using Drosophila melanogaster mosaic animals that contain cells with differing genotypes to mimic genome alterations, the effects of such somatic genetic diversity can be studied experimentally. The project examines the hypothesis that imbalances in ribosomal protein genes can trigger a 'cell competition' response that removes them in favor or other, genetically-normal cells. The domains of particular ribosomal proteins that are responsible for this additional function, beyond the well-known role of ribosomal proteins in protein synthesis, will be established using structural and functional analysis of clones genes in vivo. Particular attention will be paid to th location within the cell where ribosomal proteins are important, and to the hypothesis that ribosomal protein imbalances activate tumor suppressors of the Salvador-Hippo-Warts pathway to promote elimination of damaged cells. Genetic screens will be conducted that will identify other components of the process, and seek to identify the molecular mechanisms whereby ribosomal protein imbalance leads to cell elimination.