Modeling a cellular protein homeostasis network

细胞蛋白质稳态网络建模

• 批准号: 8560963
• 负责人: LILA M GIERASCH
• 金额: $ 42.35万
• 依托单位: UNIVERSITY OF MASSACHUSETTS AMHERST
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-05 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8560963
• 关键词: Address; Affect; Aging; Alzheimer' s Disease; Animal Model; Behavior; Biochemical; Cell Aging; Cell physiology; Cells; Code; Collaborations; Communities; Complex; Computer Simulation; Coupled; Cystic Fibrosis; Cytoplasm; Data; Disease; Drug Industry; Engineering; Enzymes; Equation; Equilibrium; Escherichia coli; Escherichia coli Proteins; Failure; Generations; Growth; Health; Heat shock proteins; Heat-Shock Response; High temperature of physical object; Homeostasis; Homologous Gene; In Vitro; Individual; Knowledge; Literature; Longevity; Malignant Neoplasms; Massachusetts; Measures; Modeling; Molecular Chaperones; Mutate; Non-Insulin-Dependent Diabetes Mellitus; Organism; Outcome; Parkinson Disease; Physiological; Physiological Processes; Play; Process; Property; Protein Biosynthesis; Proteins; Proteome; Protocols documentation; Quality Control; Reaction; Research; Research Institute; Research Personnel; Role; Set protein; Stress; System; Testing; Translations; Universities; Work; biochemical model; biological adaptation to stress; cell age; coping; improved; in vivo; insight; member; protein folding; protein misfolding; public health relevance; research study; response; therapeutic development; tool; web based interface

DESCRIPTION (provided by applicant): We propose to develop a computational model of a complete cellular protein homeostasis (proteostasis) network, including protein synthesis, degradation, folding stability, aggregation, and competing/cooperating chaperoning systems. This project is a collaboration between Lila Gierasch (University of Massachusetts Amherst) and Evan Powers (The Scripps Research Institute). Our model, called FoldEco, aims to describe the balance of biochemical and physical aspects of folding and aggregation, and their impact on the "health" of the proteins in proteomes in general, and here the proteome of the E. coli cytoplasm, in particular. FoldEco begins with the current extensive knowledge of mechanisms, biochemical circuits, and parameters, and allows for the generation of hypotheses about large-scale, complex protein folding networks under various conditions. We propose now: (1) to advance FoldEco so that it better captures the full complexity of the E. coli proteome as well as physiological processes such as the heat-shock regulatory response that play a role in proteostasis in E. coli; (2) to experimentally interrogate E. coli proteostasis under physiological conditions in order to test and ultimately improve the FoldEco model. As part of our work, we will be addressing the burden placed on the proteome by perturbation of individual proteins, how well the proteostasis network copes with such perturbations, and whether some proteins are particularly vulnerable to such perturbations. We will continue to make the FoldEco model freely available to the broad community through a web-based interface. We already have the FoldEco code in a first generation version and several experimental tests of predictions of the code. Because chaperone networks are conserved across all organisms, this work in the simple model organism, E. coli, will provide insight into protein homeostasis in higher organisms and potentially assist in the development of therapeutic strategies for protein misfolding diseases. Additionally, FoldEco will benefit the biotechnological and pharmaceutical industries where the need to produce functional proteins efficiently is critical. If successful, this work will broadly advance our ability to comprehend complex circuits that play critical roles in health and disease.

描述(由申请人提供)：我们建议开发一个完整的细胞蛋白质稳态(蛋白质稳态)网络的计算模型，包括蛋白质合成、降解、折叠稳定性、聚集和竞争/合作陪伴系统。这个项目是由Lila Gierasch(马萨诸塞大学阿默斯特分校)和Evan Power(斯克里普斯研究所)合作完成的。我们的模型名为FoldEco，旨在描述折叠和聚集的生化和物理方面的平衡，以及它们对蛋白质组中蛋白质的“健康”的影响，在这里，尤其是对大肠杆菌细胞质的蛋白质组。FoldEco从目前广泛的机制、生化电路和参数知识开始，允许在不同条件下产生关于大规模、复杂蛋白质折叠网络的假设。我们现在建议：(1)改进FoldEco，以便更好地捕捉到大肠杆菌蛋白质组的全部复杂性以及在大肠杆菌蛋白平衡中发挥作用的生理过程，如热休克调节反应；(2)在生理条件下对大肠杆菌蛋白平衡进行实验研究 以测试并最终改进FoldEco模式。作为我们工作的一部分，我们将解决单个蛋白质的扰动对蛋白质组施加的负担，蛋白质平衡网络对这种扰动的处理能力如何，以及某些蛋白质是否特别容易受到这种扰动的影响。我们将继续通过基于网络的界面向广大社区免费提供FoldEco模式。我们已经有了FoldEco代码的第一代版本，并对代码的预测进行了几次实验测试。由于伴侣网络在所有生物体中都是保守的，在简单的模式生物体--大肠杆菌中的这项工作将提供对高等生物体中蛋白质动态平衡的洞察，并有可能帮助开发蛋白质错误折叠疾病的治疗策略。此外，FoldEco将使生物技术和制药行业受益，在这些行业，高效生产功能蛋白质的需求至关重要。如果成功，这项工作将在很大程度上提高我们理解在健康和疾病中发挥关键作用的复杂电路的能力。