QSB: Quantitative Systems Approach to Hepatic Metabolism: To Elucidate the Effect of Tumor Necrosis Factor-alpha

QSB：肝脏代谢的定量系统方法：阐明肿瘤坏死因子-α 的作用

• 批准号: 0331297
• 负责人: Christina Chan
• 金额: $ 23.22万
• 依托单位: Michigan State University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-10-01 至 2006-09-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0331297&HistoricalAwards=false
• 关键词: QSB; Quantitative; Systems; Approach; Hepatic

The overall goal of this project is to develop a quantitative systems approach to elucidate the role of elevated free fatty acids and tumor necrosis factor-alpha on hepatic metabolism. Mounting evidence suggests that elevated levels of free fatty acids along with tumor necrosis factor-alpha in the plasma play an important role in regulating hepatic metabolism. Fatty acids are involved in the generation of secondary messengers for signal transduction, regulation of hepatic enzyme activity, mediators of gene expression, and storage of metabolic energy. Similarly, evidence suggests tumor necrosis factor-alpha plays a role in mediating lipid metabolism and triggers a complicated array of intracellular signals.Current mechanistic understanding of lipid metabolism is limited due to the lack of comprehensive information on the interplay of genes and proteins that may act in concert, or in opposition, in their regulation of metabolic enzymes. This short-coming is primarily due to traditional approaches, that measure a few physiological, biochemical or genetic markers, which provide limited insight into the overall molecular mechanisms involved. A "systems biology" approach reconstructs the associations that lead to a system's behavior by integrating the information derived from RNA, protein, and metabolite expression profiles as a function of its surrounding environment. The ability to quantitate expression levels of multiple genes and proteins, corresponding to a cellular metabolic state and/or environment, provides a more comprehensive and integrative approach to understanding hepatic lipid metabolism and elucidating relevant intracellular information.In summary, this project seeks to develop a quantitative framework to obtain fundamental knowledge of hepatocyte metabolism that will be subsequently applied to study the more specific aspects of Type 2 diabetes and other metabolic diseases. The quantitative framework developed in this proposal is applicable to other cellular systems.

本项目的总体目标是开发一种定量系统方法来阐明游离脂肪酸和肿瘤坏死因子-α升高对肝脏代谢的作用。越来越多的证据表明，血浆中游离脂肪酸沿着肿瘤坏死因子-α水平升高在调节肝脏代谢中起重要作用。脂肪酸参与信号转导的第二信使的产生、肝酶活性的调节、基因表达的介体和代谢能量的储存。同样，有证据表明肿瘤坏死因子-α在介导脂质代谢中起作用，并触发一系列复杂的细胞内信号。目前对脂质代谢的机制理解是有限的，因为缺乏关于基因和蛋白质相互作用的全面信息，这些基因和蛋白质可能在代谢酶的调节中协同或相反地起作用。这种不足主要是由于传统的方法，测量一些生理，生物化学或遗传标记，这提供了有限的了解所涉及的整体分子机制。“系统生物学”方法通过整合来自RNA、蛋白质和代谢物表达谱的信息，作为其周围环境的函数，重建导致系统行为的关联。定量对应于细胞代谢状态和/或环境的多个基因和蛋白质的表达水平的能力提供了更全面和综合的方法来理解肝脂质代谢并阐明相关的细胞内信息。该项目旨在开发一个定量框架，以获得肝细胞代谢的基础知识，随后将应用于研究更具体的方面2型糖尿病和其他代谢性疾病。在这个建议中开发的定量框架是适用于其他蜂窝系统。