Metabolic signals driving cell growth and proliferation

驱动细胞生长和增殖的代谢信号

• 批准号: 8050252
• 负责人: Benjamin P Tu
• 金额: $ 31.7万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8050252
• 关键词: Metabolic; signals; driving; cell; growth

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.

描述（由申请人提供）：细胞生长和增殖如何与代谢配合以及细胞的代谢状态保持不足。先前的研究已经确定，细胞必须获得足够有利的代谢状态，以启动生长和分裂计划。了解将细胞代谢与细胞生长控制联系起来的这些机制的知识将为治疗复杂的代谢疾病（例如癌症）提供新的策略。该研究建议旨在了解关键的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会在氧气消耗中进行稳健的振荡，以研究这种生长控制机制。在这些代谢周期中，当细胞氧的消耗速率大大降低时，细胞分裂精确地将其门控到时间窗口，这高度让人联想到癌细胞分裂。细胞分裂仅在完成线粒体呼吸爆发后才启动，这伴随着生长基因的短暂上调。就在进入这个生长阶段之前，细胞群体存在于类似于静止或G0的代谢阶段。有趣的是，加入精选的代谢物可以触发这个静止阶段的退出，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。 该酵母代谢周期系统将用于了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。通过调查碳源信号对生长的承诺的机制，将解决这个杰出的问题。同时，该系统将用于了解在转向生长过程中，保守的TOR生长控制途径如何变得活跃。 公共卫生相关性：我们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扩散的代谢和营养信号。我们希望这些研究能够为细胞生长控制的机制提供新的见解，并有助于我们对复杂代谢疾病（如癌症）的理解。