Metabolic signals driving cell growth and proliferation

描述（由申请人提供）：细胞生长和增殖如何与代谢协调，以及细胞的代谢状态仍然知之甚少。以前的研究已经确定，细胞必须达到足够有利的代谢状态，以启动生长和分裂程序。了解这些将细胞代谢与细胞生长控制联系起来的机制，将为治疗复杂的代谢性疾病（如癌症）提供新的策略。这项研究旨在了解关键代谢和营养信号最终控制细胞生长和增殖的机制。 一个独特的模型系统，其中一个高度同步的酵母细胞群在连续生长过程中经历了强大的氧气消耗振荡将被用来研究这种机制的生长控制。在这些代谢周期中，当细胞耗氧速率大幅降低时，细胞分裂被精确地门控到一个时间窗口，这非常令人联想到癌细胞分裂。细胞分裂只有在线粒体呼吸爆发完成后才开始，伴随着生长基因的瞬时上调。就在进入该生长期之前，细胞群存在于类似静止或G0的代谢期。有趣的是，添加选择的代谢物可以触发退出该静止期并诱导立即进入生长期。这些代谢物是生长控制途径的关键激活剂。 该酵母代谢循环系统将用于理解细胞生长和增殖如何与代谢信号和细胞代谢状态精确协调。这个突出的问题将通过调查碳源信号承诺增长的机制来解决。与此同时，该系统将用于了解保守的TOR生长控制途径如何在切换到生长期间变得活跃。 公共卫生相关性：我们已经建立了一个模型系统，这将使最终控制细胞生长和增殖的代谢和营养信号的研究。我们希望这些研究将为细胞生长控制机制提供新的见解，并有助于我们对癌症等复杂代谢疾病的理解。

DESCRIPTION (provided by applicant): How cell growth and proliferation are coordinated with metabolism and the metabolic state of a cell remains poorly understood. Previous studies have established that cells must attain a sufficiently favorable metabolic state in order to initiate a program of growth and division. Knowledge of these mechanisms that connect cellular metabolism to cell growth control will provide novel strategies for the treatment of complex metabolic diseases such as cancer. This research proposal aims to understand the mechanisms by which key metabolic and nutritional signals ultimately control cell growth and proliferation. A unique model system wherein a highly synchronized yeast cell population undergoes robust oscillations in oxygen consumption during continuous growth will be used to investigate such mechanisms of growth control. During these metabolic cycles, cell division is precisely gated to a temporal window when the rate of cellular oxygen consumption decreases substantially, which is highly reminiscent of cancer cell division. Cell division initiates only following completion of a burst of mitochondrial respiration that is accompanied by a transient upregulation of growth genes. Just prior to entry into this growth phase, the cell population exists in a metabolic phase that resembles quiescence or G0. Interestingly, addition of select metabolites can trigger exit from this quiescent phase and induce immediate entry into the growth phase. These metabolites are key activators of growth control pathways. This yeast metabolic cycle system will be utilized to understand how cell growth and proliferation are precisely coordinated with metabolic signals and cellular metabolic state. This outstanding problem will be addressed by investigating the mechanisms by which carbon sources signal commitment to growth. In parallel, this system will be used to understand how the conserved TOR growth control pathway becomes active during the switch to growth. PUBLIC HEALTH RELEVANCE: We have established a model system that will enable the study of the metabolic and nutritional signals that ultimately control cell growth and proliferation. We hope these studies will provide novel insights into the mechanisms of cell growth control and contribute towards our understanding of complex metabolic diseases such as cancer.