Cell Competition in Development and Homeostasis

该项目的目标是阐明保护单个细胞遗传完整性的机制。DNA 导致单个细胞中基因数量改变的损伤在肿瘤中非常常见， 他们的进步。人们认为，随着时间的推移，体内的许多细胞也会发生类似的损伤。确实这样的 损伤可能是衰老过程的标志，也是与年龄有关的疾病的诱因， 痴呆症、心血管疾病和糖尿病，以及癌症。利用果蝇 嵌合体动物含有不同基因型的细胞，以模拟基因组的改变， 体细胞遗传多样性可以通过实验进行研究。该项目研究了以下假设： 核糖体蛋白质基因的不平衡会引发“细胞竞争”反应， 或者其他基因正常的细胞。负责这一过程的特定核糖体蛋白的结构域 除了核糖体蛋白在蛋白质合成中的众所周知的作用之外， 使用克隆基因的结构和功能分析在体内建立。将特别注意 核糖体蛋白在细胞内的重要位置，以及核糖体蛋白在细胞内的重要位置的假设， 蛋白质失衡激活Salvador-Hippo-Warts途径的肿瘤抑制因子，促进消除 受损的细胞。将进行基因筛选，以确定该过程的其他组成部分， 试图确定核糖体蛋白质失衡导致细胞消除的分子机制。

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 the 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.