Assessing Effects of Genetics and Environment on Metabolism in S cerevisiae

描述（由申请人提供）：代谢包括细胞从营养物质产生能量和其他必需分子的所有过程。这些途径依赖于数百个基因，并涉及数千个小分子中间体，维生素和辅因子。代谢物的小规模分析已经是临床诊断的常见实践。对小分子的兴趣增加导致了允许代谢中间体的高通量分析的技术的发展。这些方法已经导致了肾癌的新诊断技术。为了进一步了解小分子代谢物的作用，我已经开始使用毛细管电泳来分析酿酒酵母中的代谢物。酵母与人类共享所有主要代谢途径，并提供了充分研究的模式生物的优势。基于相似性，酵母的结果可以很容易地转化为人类生物学。初步研究表明，这种分析方法是简单的，定量和易于实现自动化。首先，我将确定衍生试剂，使我能够观察到各种各样的代谢物。第二，我将描述酵母基因，影响细胞代谢物的水平相关的基本代谢途径。第三，我将在对环境刺激的反应和细胞过程（如细胞周期）期间分析代谢物。第四，我将使用酵母来确定人类基因的多态性如何影响人类代谢中的这些途径。这些数据将为酵母和人类的代谢网络提供更清晰的图像，从而深入了解人类健康和疾病中代谢过程的生物学。公共卫生相关性：新陈代谢的基本过程位于细胞生物学的每个过程之下。通过检查和了解细胞对刺激的代谢反应，我们将深入了解各种生物过程。此外，将正常细胞变化与受癌症或糖尿病影响的细胞发生的变化进行比较，为疾病预防和治疗提供了一种潜在的新机制。

DESCRIPTION (provided by applicant): Metabolism encompasses all the processes by which a cell generates energy and other essential molecules from nutrients. These pathways rely on hundreds of genes and involve thousands of small molecule intermediates, vitamins and cofactors. Small-scale analysis of metabolites is already a common practice for clinical diagnosis. Increased interest in small molecules has led to development of technologies that allow high-throughput profiling of metabolic intermediates. These methods have already led to new diagnostic techniques for kidney cancer. To further our understanding of the roles for small molecule metabolites, I have begun using capillary electrophoresis to profile metabolites in the yeast Saccharomyces cerevisiae. Yeast share all major metabolic pathways with humans and provide the advantages of a well-studied model organism. Based on the similarities, results in yeast can be easily translated to human biology. Preliminary studies demonstrate that this profiling method is simple, quantitative and easily amenable to automation. First, I will identify derivatization reagents that allow me to observe a wide variety of metabolites. Second, I will characterize yeast genes that affect the levels of cellular metabolites relevant to essential metabolic pathways. Third, I will profile metabolites during response to environmental stimuli and during cellular processes such as the cell cycle. Fourth, I will use yeast to determine how polymorphisms in human genes affect these pathways in human metabolism. These data will provide a clearer picture of the metabolic network in yeast and human, yielding insights into the biology of metabolic processes in human health and disease. PUBLIC HEALTH RELEVANCE: The basic processes of metabolism lie beneath every process of cell biology. By examining and understanding a cell's metabolic response to stimuli, we will gain insights into diverse biological processes. In addition, comparing normal cellular changes with the changes that occur during cells affected by cancer or diabetes provides a potentially novel mechanism for disease prevention and treatment.