Cell competition in development and homeostasis

控制细胞功能的许多方面的基因包含在细胞核中的染色体上。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就会改变。基因和染色体的改变会导致出生缺陷，在衰老过程中积累，几乎在每一种癌症中都有发现，而且被认为对健康有许多不利影响。这一假说认为，分散在不同染色体周围的一组80个基因被用来识别具有大规模遗传变化的细胞，并在它们影响健康之前将其消除。这些基因编码核糖体蛋白，每一个都在核糖体中组装成一个独特的位置，因此，如果有任何限制，核糖体的组装就会受到影响。对果蝇的研究记录了一条由核糖体蛋白基因失衡激活的调控途径，并通过与附近正常细胞的竞争导致细胞消除。本研究的目的之一是验证核糖体蛋白基因，以及对其失衡作出反应的调控基因，能够靶向具有遗传损伤的细胞进行竞争性消除，并确定体细胞组织中受这种调控机制影响的基因组损伤范围。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遗传变化中的作用。这些研究利用果蝇染色体的靶向基因重组方法。这些研究将确立一种新认识的机制的重要性和范围，这种机制可以清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，以及在健康衰老和预防年龄相关疾病中发挥重要作用。

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.