Modeling and Analysis of Yeast Sphingolipid Metabolism

描述(申请人摘要)：最近发生了一起爆炸事件 脂质介导的信号转导和细胞调控的研究。这个 压倒一切的模式专注于模块化信号传递，即一种刺激 调节一种酶，产生一种活性分子。 然而，脂肪代谢的复杂性远远超过了简单的 单个信号模块，使得一个激动剂可以调节多个 酶或一种酶的生物活性产物(如神经酰胺)可用作 产生不同生物活性分子的另一种酶的底物 甘油二酯或鞘氨醇)。因此，我们假设，这种复杂性 脂肪代谢主要用于提供高度调节和协调的 具有不同和重叠功能的生物活性分子网络。这些 然后，网络用于整合和协调细胞对 各种试剂和环境刺激物。将对这一假设进行调查 在酿酒酵母中，专注于基因表达反应(通过微阵列 表达)，因为它们与鞘脂新陈代谢有关。我们将发展和 应用酵母反应的数学模型，并使用以下组合 根据以下具体目标采用生化和遗传方法：1) 预测酿酒酵母对神经鞘糖脂的生物活性 酵母转录反应分析中的特异性刺激(表达 鞘磷脂代谢酶)对这些刺激；2)模拟海藻糖 热应激反应的代谢和糖酵解及其与 鞘磷脂代谢；以及3)预测细胞对不同类型的 来自生物活性脂类的刺激。这些研究将为 为全球模型奠定基础，在该模型中，我们可能能够预测特定的 受鞘脂调节的转录途径/模块，并预测 神经鞘脂对特定构型的整体遗传反应 级别。这个模型系统可以作为一个概念性的和实践性的 平台将假设扩展到其他类脂类，其他方面 调节新陈代谢，最终达到哺乳动物的新陈代谢。

DESCRIPTION (applicant's abstract): There has been a recent explosion in the study of lipid mediated signal transduction and cell regulation. The over-riding paradigm has focused on modular signaling whereby one stimulus regulates one enzyme resulting in the generation of one active molecule. However, the complexity of lipid metabolism far exceeds a simple collection of individual signaling modules such that one agonist may regulate several enzymes, or the bioactive product of one enzyme (e.g. ceramide) may serve as a substrate for another enzyme generating a different bioactive molecule (such as diacyiglycerol or sphingosine). Thus, we hypothesize that this complexity of lipid metabolism serves primarily to provide a highly regulated and coordinated network of bioactive molecules with distinct and overlapping functions. These networks then serve to integrate and coordinate complex responses of cells to various agents and environmental stimuli. This hypothesis will be investigated in S. cerevisiae, focusing on gene expression responses (by microarray expression) as they relate to sphingolipid metabolism. We will develop and apply mathematical modeling of yeast responses and use a combination of biochemical and genetic approaches according to the following specific aims: 1) predicting the bioactive sphingolipid profile of S. cerevisiae in response to specific stimuli from analysis of transcription responses of yeast (expression of enzymes of sphingolipid metabolism) to these stimuli; 2) modeling trehalose metabolism and glycolysis in response to heat stress and relate it to sphingolipid metabolism; and 3) predicting specific cell responses to various stimuli from the profile of bioactive lipids. These studies will lay the groundwork for a global model in which we may be able to predict specific transcription pathways/modules that are regulated by sphingolipids, and predict the overall genetic response to a specific configuration of sphingolipid levels. This model system could then serve as a conceptual and practical platform to extend the hypothesis to other lipid classes, other aspects of regulated metabolism, and eventually to mammalian metabolism.