Transcriptional Integration of Metabolism

描述(申请人提供)：代谢途径相互错综复杂地相互协调，并与外部环境相协调，以确保生物合成、能量生产和分解代谢的小分子正确流动。许多人类疾病，糖尿病、代谢综合征和癌症是最常见的三种，都与未能正确调节代谢活动有关。此外，衰老和新陈代谢是相互联系的，从酵母到人类，各种生物的卡路里限制效应都表明了这一点。因此，更清楚地了解新陈代谢的调节对于改善人类健康和战胜疾病具有重要意义。 新陈代谢在所有水平上都受到调节，从转录对基因表达的影响到翻译后修改环境信号。调节编码代谢酶的基因的转录使细胞能够增加或降低代谢酶的水平，并对环境变化提供更持久或更强大的反应。葡萄糖是所有细胞的主要能量和碳源，葡萄糖的耗尽是许多代谢哺乳动物AMP激活的蛋白激酶的共同触发因素，这些蛋白激酶可以感知各种类型的应激，包括低糖。SNF1协调转录因子和其他调节蛋白的表达和活性，这些转录因子和其他调节蛋白调节代谢途径中的基因表达，使细胞在没有葡萄糖的情况下继续生长。使用DNA微阵列的基因表达分析，以及使用染色质免疫沉淀的转录因子定位，将识别将调节蛋白连接到特定代谢途径的途径。通过气相色谱和质谱联用对小分子稳态水平的代谢谱分析，可以确定受转录因子调控的未知ORF影响的代谢途径，这些转录因子在葡萄糖耗尽时是活跃的。

DESCRIPTION (provided by applicant): Metabolic pathways are intricately coordinated with each other and with the external environment to insure the correct flow of small molecules for biosynthesis, energy production, and catabolism. Many human pathologies, diabetes, metabolic syndrome, and cancer being three of the most common, are associated with the failure to correctly regulate metabolic activities. In addition, aging and metabolism are interconnected as shown by the effects of calorie restriction in organisms ranging in diversity from yeast to humans. Thus, gaining a clearer understanding of the regulation of metabolism has important implications for bettering human health and overcoming disease. Metabolism is regulated at all levels, from transcription effects on gene expression to post-translational modifying environmental signals. Regulating transcription of the genes encoding metabolic enzymes allows the cells to increase or decrease the level of metabolic enzymes and provides a longer-lasting or more robust response to environmental change. Depletion of glucose, the primary energy and carbon source for all cells, is a common trigger for many metabolic mammalian AMP-activated protein kinase that senses various types of stress, including low glucose. Snf1 coordinates the expression and activity of transcription factors and other regulatory proteins that modulate the expression of genes acting in metabolic pathways that allow the cell to continue to grow in the absence of glucose. Gene expression analysis using DNA microarrays, and transcription factor localization using chromatin immunoprecipitation, will identify the pathways connecting regulatory proteins to specific metabolic pathways. Metabolic profiling of the steady-state levels of small molecules by coupled gas chromatography and mass spectrometry will identify the metabolic pathways influenced by unknown ORFs regulated by transcription factors that are active when glucose is depleted.