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

该项目的总体目标是开发一种定量系统方法来阐明升高的游离脂肪酸和肿瘤坏死因子-α在肝脏代谢中的作用。越来越多的证据表明，血浆中游离脂肪酸和肿瘤坏死因子-α水平的升高在调节肝脏代谢方面发挥了重要作用。脂肪酸参与了信号转导、肝酶活性的调节、基因表达的中介和代谢能量的储存等次级信使的产生。同样，有证据表明，肿瘤坏死因子-α在调节脂质代谢中发挥作用，并触发一系列复杂的细胞内信号。由于缺乏全面的信息，在调节代谢酶过程中可能协同或相反作用的基因和蛋白质之间的相互作用，目前对脂代谢的机制理解是有限的。这一缺陷主要是由于传统的方法，这些方法测量一些生理、生化或遗传标记，对所涉及的整体分子机制的洞察有限。“系统生物学”方法通过将来自RNA、蛋白质和代谢物表达谱的信息作为其周围环境的函数来重建导致系统行为的关联。能够量化多个基因和蛋白质的表达水平，与细胞的代谢状态和/或环境相对应，为了解肝脏脂肪代谢和阐明相关的细胞内信息提供了更全面和综合的方法。综上所述，该项目寻求建立一个定量框架来获得肝细胞代谢的基础知识，随后将其应用于研究2型糖尿病和其他代谢性疾病的更具体的方面。本提案中提出的量化框架也适用于其他蜂窝系统。

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.