Control of cell cycling speed to delay the onset of senescence

描述（由申请人提供）：一些疾病的发病率——包括癌症——随着年龄的增长而增加。衰老过程与细胞循环有着复杂的关系：细胞循环通过确保自我更新来维持器官功能，但这种循环被认为会驱动突变积累，并最终导致衰老。我们的长期目标是阐明动物使用的策略，以尽量减少细胞循环的负面影响，并阐明自我更新和突变累积之间的妥协。我们使用秀丽隐杆线虫生殖系作为模型系统，因为四个关键特征使它独特地适合解决这些问题。首先，它经历了连续的细胞更新，细胞增殖弥补了配子体发生中细胞的损失；这使得它成为自我更新器官的合适模型系统，如肠道，这是癌症的一个重要原因。其次，它简单的空间组织——细胞按照分化的梯度线性排列——使得定量表征循环生殖细胞亚群之间的细微差异变得简单明了。第三，强大的秀丽隐杆线虫遗传学已经确定了生殖细胞的许多分子控制，并提供了精细操纵这些控制的工具。重要的是，许多自我更新和细胞周期的控制——如Notch、Cyclin E和Pumilio同源物fbf-1和fbf-2——在包括人类在内的其他动物中具有保守的功能。第四，生殖系在短时间内（约1周）经历衰老，这使得衰老实验变得可行。我们的研究将追求三个相关的目标。首先，我们将确定细胞周期速度的分子控制，建立在先前的工作基础上，已经确定了正常细胞周期进程所需的分子成分。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，扰乱它们的表达，并测定对细胞循环速度的影响。其次，我们将分析细胞周期和生殖衰老的发生之间的关系。第三，我们将询问秀丽隐杆线虫生殖腺实施了哪些细胞周期控制策略来延缓衰老的发生；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。我们将从理论角度解决这些策略，使用计算机模拟来阐明它们的好处，并从实验角度解决这些策略，使用精心设计的实验来揭示性腺采用的以前未被认识的策略。总的来说，我们的研究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：在细胞亚群中精细控制细胞周期速度以延缓衰老的发生。

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.