The incidence of a number of diseases - including cancer - increases with age. The aging process has a complex relationship with cell cycling: cell cycling maintains organ function by ensuring self-renewal, but this cycling is thought to drive mutation accumulation, and to eventually lead to senescence. Our long-term aim is to elucidate the strategies used by animals to minimize the negative impact of cell cycling, and to elucidate the compromises made between self-renewal and mutation accrual. We use the C. elegans germ line as a model system because four key features make it uniquely suitable to address these problems. First, it undergoes continuous cell turnover, with cell proliferation compensating for the loss of cells to gametogenesis;this makes it a suitable model systems for self-renewing organs, such as the intestine, that are an important cause of cancer. Second, its simple spatial organization - with cells laid out linearly according to a gradient of differentiation - makes it straightforward to quantitatively characterize fine differences between subpopulations of cycling germ cells. Third, powerful C. elegans genetics have identified a number of molecular controls of germ cells, and provide tools to finely manipulate these controls. Importantly, many of the controls of self-renewal and cell cycling - such as Notch, Cyclin E, and the Pumilio homologues fbf-1 and fbf-2 - have conserved functions in other animals, including humans. Fourth, the germ line undergoes senescence over a short period of ~1 week that makes aging experiments practical. Our research will pursue three related aims. First, we will identify molecular controls f cell cycling speed, building on previous work that has identified molecular components necessary for normal cell cycle progression. We will finely quantify expression of these components using computational tools we have developed, perturb their expression, and assay the effect on cell cycling speed. Second, we will assay the relationship between cell cycling and the onset of reproductive senescence. Third, we will ask what cell cycle control strategies are implemented by the C. elegans gonad to delay the onset of senescence;we will in particular focus on strategies that anticipate the future rate of cell turnover to optimize cell cycle parameters. We will address these strategies both from a theoretical angle, using computer simulations to elucidate their benefits, and from an experimental angle, using experiments crafted to uncover previously-unrecognized strategies employed by the gonad. Overall, our results will reveal how stem cell regulatory networks attain an important performance objective: fine control of cell cycle speed across subpopulations of cells to delay the onset of senescence.
Links between cell cycling and senescence are known, but we are still missing a systems-level understanding of the objectives and constraints that underlie the tradeoffs made by biological systems. With the proposed research, we will gain insights into cell cycle control strategies used by animals - and in particular humans - to delay the onset of senescence and of diseases such as cancer.
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