Abstract 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 signal that is activated by ribosomal protein gene imbalance and that leads to cell elimination by cell competition with nearby normal cells, and they have identified signaling proteins that are involved. One goal of this proposal is to verify that ribosomal protein genes, and the signaling proteins that respond to their imbalance, are able to target cells with genetic damage for competitive elimination, and to document the range and extent of genetic damage to which this applies. These studies make use of targeted genetic recombination methods using fruitfly chromosomes. A second goal is to establish the molecular mechanisms of the signaling process that responds to ribosomal protein imbalance. These studies use molecular genetic and molecular biology methods to study mechanisms of gene expression regulation. The final goal is to explore whether corresponding proteins act to eliminate cells with large-scale genetic changes from mammalian tissues. These studies use newly-generated mutant mouse strains and custom techniques to count chromosome numbers in developing mouse tissues. These studies represent the initial characterization of a pathway 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.
|Effective start/end date||9/15/19 → 8/31/20|
- National Institute of General Medical Sciences: $334,667.00