Metabolic signals driving cell growth and proliferation

描述(申请人提供)：细胞生长和增殖如何与新陈代谢相协调，以及细胞的新陈代谢状态仍然知之甚少。以前的研究已经证实，细胞必须达到足够有利的代谢状态，才能启动生长和分裂计划。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癌症等复杂代谢性疾病的治疗提供新的策略。这项研究计划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，其中高度同步的酵母细胞种群在连续生长过程中经历强劲的氧气消耗振荡，将被用于研究这种生长控制机制。在这些代谢周期中，当细胞耗氧率大幅下降时，细胞分裂被精确地门控到一个时间窗口，这很容易让人联想到癌细胞分裂。细胞分裂只有在线粒体呼吸完成后才开始，线粒体呼吸伴随着生长基因的瞬时上调。就在进入这一生长阶段之前，细胞群体处于类似于静止或G0的代谢阶段。有趣的是，添加精选的代谢物可以触发退出这一静止阶段，并诱导立即进入生长阶段。这些代谢物是生长控制途径的关键激活剂。这个酵母代谢循环系统将被用来理解细胞生长和增殖是如何与代谢信号和细胞代谢状态精确协调的。这个悬而未决的问题将通过调查碳源发出增长承诺信号的机制来解决。同时，这个系统将被用来理解保守的TOR生长控制途径在转换到生长过程中是如何变得活跃的。 与公共健康相关：我们已经建立了一个模型系统，该系统将能够研究最终控制细胞生长和增殖的代谢和营养信号。我们希望这些研究将为细胞生长控制的机制提供新的见解，并有助于我们理解复杂的代谢性疾病，如癌症。

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.