Cell competition in development and homeostasis

控制细胞许多方面功能的基因包含在细胞核的染色体上。如果这些基因或携带它们的染色体受损，细胞功能的许多方面都可能改变。基因和染色体的变化会导致出生缺陷，随着年龄的增长而积累，几乎在每一种癌症中都能发现，并被认为对健康有许多不利影响。这项提议假设，一组分布在不同染色体上的80个基因被利用来识别具有大规模基因变化的细胞，并在它们影响健康之前消除它们。这些基因编码核糖体蛋白，每个蛋白在核糖体中组装成一个独特的位置，因此如果有任何限制核糖体组装的影响。对果蝇的研究证明，核糖体蛋白基因失衡激活了一条调控途径，导致细胞通过与附近正常细胞的竞争而被消除。这项提案的一个目标是验证核糖体蛋白基因和对其失衡做出反应的调控基因是否能够针对具有基因损伤的细胞进行竞争性消除，并确定在体细胞组织中受这种调控机制影响的基因组损伤的范围。第二个目标是评估细胞竞争在保护生殖系免受可能导致出生缺陷的非整倍体基因变化的影响方面的作用。这些研究利用了利用果蝇染色体的定向基因重组方法。这些研究将确定一种新认识的机制的重要性和范围，该机制可以移除具有大规模遗传损伤的细胞，并可能在预防出生缺陷和癌症以及在健康老龄化和预防与年龄相关的疾病方面发挥重要作用。

The genes that control many aspects of cellular function are contained on chromosomes in the cell nucleus. If these genes or the chromosomes that carry them become damaged, many aspects of cell function can be altered. Gene and chromosome changes can cause birth defects, accumulate during aging, are found in nearly every cancer, and are thought to have many adverse effects on health. This proposal hypothesizes that a set of 80 genes, dispersed around the various chromosomes, are exploited to recognize cells with large-scale genetic changes and eliminate them before they affect health. These genes encode ribosomal proteins, each one of which assembles into a unique position in the ribosome, so that ribosome assembly is affected if any are limiting. Studies in the fruitfly Drosophila document a regulatory pathway that is activated by ribosomal protein gene imbalance and that leads to cell elimination by cell competition with nearby normal cells. One goal of this proposal is to verify that ribosomal protein genes, and the regulatory genes that respond to their imbalance, are able to target cells with genetic damage for competitive elimination, and to define the range of genome damage that is subject to this regulatory mechanism in somatic tissues. A second goal is to assess the role of cell competition in protecting the germline from aneuploid genetic changes that might lead to birth defects. These studies make use of targeted genetic recombination methods using fruitfly chromosomes. These studies will establish the importance and scope of a newly-recognized mechanism that can remove cells with large-scale genetic damage, and which may play an important role in the prevention of birth defects and of cancer, as well as in healthy aging and prevention of age-related diseases.