A Genome-Scale Regulated Metabolic Model of Yeast

描述(由申请人提供)： 该研究计划的目标是利用现有的遗传/生化文献和数据以及该计划内产生的实验数据，建立酿酒酵母代谢、调节和大分子合成的基因组规模的电子模型。该模型还将用于驱动预期的实验设计，并将执行这些实验来审问该模型。基因组学和各种高通量技术正在产生大量关于活细胞的分子数据。这些数据和细胞过程的复杂性现在要求在硅胶模型中构建大规模(最终是基因组规模)的模型，以便在生物体的全部细胞功能的背景下解释数据。拟议的研究计划由三个具体目标组成：#1基于单个细胞成分的现有数据，建立描述新陈代谢及其调节以及蛋白质合成过程的酵母基因组规模模型；#2生成高通量功能基因组数据，以持续的方式扩展和验证该模型；以及#3对敲除菌株进行模型驱动的靶向表型分析，以验证或驳斥该模型。将用于在AIM#2中重建网络的数据类型是全基因组转录图谱和DNA结合位点识别(位置分析)数据。这些实验将以模型驱动的方式设计，以允许对现有模型进行有效验证和扩展。最后，模型将通过执行高通量和详细的表型实验来验证，这些实验旨在最佳地探测模型的不一致性或不准确性。酿酒酵母是一种重要的基础医学研究的真核模式生物，具有重要的工业意义。这种生物的基因组规模模型有望对系统生物学的发展产生广泛的影响，并具有广泛的实用价值。拟议中的计划将导致开发出第一个真核生物基因组规模的综合模型，并将作为建立包括老鼠和人类在内的高等真核生物的类似模型的垫脚石。

DESCRIPTION (provided by applicant): The goal of this research program is to develop a genome-scale in silico model of metabolism, its regulation, and macromolecular synthesis in Saccharomyces cerevisiae using existing genetic/biochemical literature and data as well as experimental data generated within the program. The model will also be used to drive prospective experimental designs, and these experiments will be performed to interrogate the model. Genomics and various high-throughput technologies are generating large volumes of molecular data on living cells. This data and the complexity of cellular processes are now demanding the construction of large-scale (ultimately genome-scale) in silico models in order to interpret the data in the context of the full cellular function of an organism. The proposed research program is comprised of three specific aims: #1 to build a genome-scale model of yeast that describes metabolism and its regulation along with the protein synthesis process based on data available on the individual cellular components; #2 to generate high-throughput functional genomics data to expand and validate the model in an on-going fashion; and #3 to perform modeldriven targeted phenotyping of knock-out strains to validate or refute the model. The data types that will be used to reconstruct the network in Aim #2 are genome-wide transcription profiling and DNA-binding site identification (location analysis) data. These experiments will be designed in a model-driven fashion to allow efficient validation and extension of the existing model. Finally, the model will be validated by performing both high-throughput and detailed phenotyping experiments designed to optimally probe the model for inconsistencies or inaccuracies. S. cerevisiae is an important eukaryotic model organism for basic medical research and of great industrial significance. A genome-scale model of this organism is expected to have wide impact on the development of systems biology and be of broad practical use. The proposed program would result in the development of the first genome-scale integrated model of a eukar-yotic organism and would serve as a stepping stone for building similar models of higher eukaryotes including mouse and human.