Control of cell cycling speed to delay the onset of senescence

描述(申请人提供)：许多疾病--包括癌症--的发病率随着年龄的增长而增加。衰老过程与细胞周期有着复杂的关系：细胞周期通过确保自我更新来维持器官功能，但这种周期被认为驱动突变积累，并最终导致衰老。我们的长期目标是阐明动物用来将细胞周期的负面影响降至最低的策略，并阐明自我更新和突变增加之间的妥协。我们使用线虫生殖系作为模型系统，因为四个关键特征使其独特地适合于解决这些问题。首先，它经历了持续的细胞更替，细胞增殖弥补了配子发生所造成的细胞损失；这使得它成为自我更新器官的合适模型系统，如肠道，这是癌症的重要原因。其次，它简单的空间组织--细胞根据分化的梯度线性排列--使得它可以直接定量地表征循环生殖细胞亚群之间的细微差异。第三，强大的线虫遗传学已经确定了生殖细胞的一些分子控制，并提供了精细操纵这些控制的工具。重要的是，许多对自我更新和细胞周期的控制--如Notch、Cyclin E以及Pumilio同系物fbf-1和fbf-2--在包括人类在内的其他动物中都具有保守的功能。第四，胚系在短短一周的时间内就会衰老，这使得老化实验变得可行。我们的研究将追求三个相关目标。首先，我们将确定细胞周期速度的分子控制，建立在以前工作的基础上，确定了正常细胞周期进程所必需的分子成分。我们将使用我们开发的计算工具精细地量化这些成分的表达，干扰它们的表达，并分析它们对细胞周期速度的影响。其次，我们将分析细胞周期与生殖衰老的关系。第三，我们将询问线虫性腺实施了哪些细胞周期控制策略来延缓衰老的开始；我们将特别关注预测未来细胞周转率的策略，以优化细胞周期参数。我们将从理论角度讨论这些策略，使用计算机模拟来阐明它们的好处，并从实验角度，使用精心设计的实验来揭示以前未被识别的性腺使用的策略。总体而言，我们的结果将揭示干细胞调控网络如何实现一个重要的性能目标：精细控制不同细胞亚群的细胞周期速度，以延缓衰老的开始。

DESCRIPTION (provided by applicant): 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.