Metabolic Control in a Dynamic Environment

动态环境中的代谢控制

• 批准号: 7260711
• 负责人: JEFF M HASTY
• 金额: $ 28.34万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7260711
• 关键词: Adopted; Affect; Back; Biochemical Pathway; Carbon; Cell Proliferation; Cells; Code; Complex; Computer Simulation; Condition; Data; Data Analyses; Development; Disease; Environment; Enzymes; Eukaryota; Eukaryotic Cell; Facility Construction Funding Category; Feedback; Fluorescence; Frequencies; Galactose; Gene Expression; Gene Expression Regulation; Generations; Genes; Goals; Human; Knowledge; Lead; Metabolic; Metabolic Control; Metabolism; Microfluidic Microchips; Microfluidics; Modeling; Molecular; Molecular Biology; Monitor; Nature; Nutrient; Nutritional; Operative Surgical Procedures; Pathology; Process; Proteins; Regulation; Regulator Genes; Research Personnel; Role; Saccharomyces cerevisiae; Signal Transduction; Son; Source; Staging; System; Techniques; Testing; Transcription Coactivator; Transcriptional Regulation; Yeasts; cell growth; design; design and construction; environmental change; extracellular; feeding; insight; programs; research study; response; size; synthetic biology

DESCRIPTION (provided by applicant): In order to optimally control such functions as cellular growth and proliferation, cells must be able to efficiently respond to a dynamically changing environment. For instance, the metabolic response of a cell to changes in nutrient levels requires transcriptional control of metabolic enzymes. This project will quantitatively explore the response of a well-characterized yeast metabolic network to a dynamically changing environment, and will provide general insights into the response of a gene regulatory network to external perturbations. Since galactose utilization networks are common to many higher eukaryotes, and altered expression of essential metabolic enzymes in humans can lead to disease, these studies will also yield insights into the mechanisms of metabolic pathologies. Using experimental synthetic biology techniques, in combination with computational modeling, we will design and construct increasingly complex gene regulatory networks that control cellular metabolism. These networks will be examined at the single-cell level using customized microfluidic devices, in conjunction with fluorescence microsopy. At each stage we will examine the response of different feedback mechanisms to environmental perturbations. The general hypothesis underlying the specific aims is that gene-regulatory feedback loops are responsible for precisely tuning the metabolic response to nutritional fluctuations. The first aim will involve studying an isolated metabolic gene without feedback to yield a quantitative understanding of how unregulated networks respond to a changing environment. In the second aim, a negative feedback regulatory module will be constructed and studied to determine how negative feedback can dampen the effects of undesirable nutritional fluctuations. In the third aim, a positive feedback regulatory module will be constructed and studied to determine how positive feedback can increase the sensitivity to environmental nutrient shifts. In the final aim, both the positive and negative feedback modules will be combined to study how the metabolic network responds to environmental fluctuations as a whole. These studies will provide crucial insights into the elaborate mechanisms by which a regulatory network responds to dynamically changing environmental conditions.

描述（由申请人提供）：为了最佳地控制诸如细胞生长和增殖的功能，细胞必须能够有效地响应动态变化的环境。例如，细胞对营养水平变化的代谢反应需要代谢酶的转录控制。该项目将定量探索一个特征良好的酵母代谢网络对动态变化的环境的响应，并将提供对基因调控网络对外部扰动的响应的一般见解。由于半乳糖利用网络是许多高等真核生物所共有的，并且人类必需代谢酶的表达改变可能导致疾病，因此这些研究还将深入了解代谢病理学的机制。使用实验合成生物学技术，结合计算建模，我们将设计和构建越来越复杂的基因调控网络，控制细胞代谢。这些网络将在单细胞水平上使用定制的微流控装置结合荧光显微镜进行检查。在每个阶段，我们将研究不同的反馈机制对环境扰动的反应。这些特定目标背后的一般假设是，基因调节反馈回路负责精确地调整代谢对营养波动的反应。第一个目标是研究一个没有反馈的孤立的代谢基因，以定量地了解不受调控的网络如何对不断变化的环境做出反应。在第二个目标中，将构建和研究负反馈调节模块，以确定负反馈如何抑制不良营养波动的影响。在第三个目标中，将构建和研究正反馈调节模块，以确定正反馈如何增加对环境养分变化的敏感性。在最终的目标中，正反馈和负反馈模块将被结合起来，以研究代谢网络如何响应环境波动作为一个整体。这些研究将为监管网络对动态变化的环境条件做出反应的复杂机制提供重要见解。