National Center for Quantitative Biology of Complex Systems

国家复杂系统定量生物学中心

• 批准号: 10089073
• 负责人: JOSHUA J COON
• 金额: $ 28.19万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-05 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10089073
• 关键词: Acylation; Affect; Animal Model; Area; Automobile Driving; Bioenergetics; Biological; Biology; Biotechnology; Cell physiology; Cells; Collaborations; Communities; Complex; Coupled; Development; Genes; Genetic; Genomics; Goals; Heart failure; Hydroxylation; Individual; Knowledge; Learning; Link; Lipids; Malignant Neoplasms; Measurement; Measures; Metabolic; Metabolism; Methylation; Mission; Modification; Nucleic Acids; Output; Phenotype; Phosphorylation; Physiology; Population Heterogeneity; Post-Translational Protein Processing; Procedures; Process; Proteins; Proteomics; Provider; Publications; RNA; Renaissance; Research Personnel; Resources; Scientist; Shoulder; Signal Transduction; Signaling Protein; Surface; System; Technology; Testing; Work; experience; glycosylation; human genome sequencing; innovation; interest; multiple omics; new technology; next generation sequencing; protein degradation; protein expression; protein function; recruit; success; technological innovation; technology development

PROJECT SUMMARY – DRIVING BIOMEDICAL PROJECTS The high-level goals of our Resource are to accelerate the pace, depth, and accuracy of protein and PTM quantification, and to empower the scientific community to make new, impactful discoveries with these technologies. Initially, our TR&Ds were influenced by a clear need in the broad field of metabolism for new technologies that could accelerate discovery. Using our expertise in this field, we recruited world-class scientists who devised projects that served as robust testbeds for our TR&Ds. Many of these projects have been driven to completion while others have remained active and have influenced new TR&Ds. These interactions – and the broad utility of our technologies – have led to a natural expansion of our focus areas. We have also become better calibrated on our capabilities and bandwidth, allowing us to shoulder a broad swath of projects with efficiency and high success rates. For Cycle 2, two overarching DBP themes motivate our Resource’s technology development: Theme 1. New, metabolite-derived post-translational modifications (PTMs). The ability of PTMs such as phosphorylation and ubiquitylation to regulate signaling and protein turnover has long been established, and we have accelerated discoveries in this space through our original DBPs. Now, the scientific community is experiencing a renaissance of interest in how understudied modifications exert control over protein function in diverse cell biological contexts. These include methylation, acylation, glycosylation, and hydroxylation. Additionally, modifications to other biological species, such as glycosylated nucleic acids, are emerging as exciting, unexplored areas of biology. Many of these modifications are directly derived from central metabolites, thus intimately linking them to the metabolic state of the cell. Theme 2. Large-scale systems and multi-omics analyses to explore physiology and metabolism. The sequencing of the human genome, a watershed moment for biology, set a framework for deep understanding of genes and their functions. Next-generation sequencing has greatly accelerated our ability to measure the expression levels of these genes, thereby giving us a surface- level understanding of how cellular processes are changing under contrasting states. Nonetheless, myriad large- scale analyses have revealed a marginal protein/RNA correlation (R ~ 0.5), demonstrating the need for protein measurements of comparable depth and precision. Similarly, comprehensive analyses of lipid and metabolite abundance have revealed that protein expression alone is insufficient to predict metabolite levels, which are further affected by protein modifications and substrate availability, among other influences. Collectively, these observations have mandated the development of integrated, multi-omic analyses that provide a more holistic picture of a biological state.

项目摘要-推动生物医学项目 我们资源的高级目标是加快蛋白质和PTM的速度、深度和准确性 量化，并使科学界能够利用这些新的、有影响力的发现 技术。最初，我们的研发和开发受到新的新陈代谢领域的明显需求的影响。 可以加速发现的技术。利用我们在这一领域的专业知识，我们聘请了世界一流的科学家 世卫组织设计的项目为我们的研发提供了强大的试验台。这些项目中的许多已经被驱使到 其他国家则保持活跃，并对新的研发产生了影响。这些互动--以及 我们技术的广泛实用性--导致了我们重点领域的自然扩展。我们也成为了 更好地校准我们的能力和带宽，使我们能够承担广泛的项目 高效率和高成功率。在周期2中，两个主要的DBP主题激励我们的资源的技术 发展：主题1.新的代谢物衍生的翻译后修饰(PTM)。PTMS的能力 如调节信号和蛋白质周转的磷酸化和泛素化早已确立， 我们通过我们最初的DBP加速了这一领域的发现。现在，科学界正在 经历了对未被研究的修饰如何对蛋白质功能进行控制的兴趣的复兴 不同的细胞生物学背景。这些包括甲基化、酰化、糖基化和羟化。 此外，对其他生物物种的修饰，如糖基化核酸，正在成为 令人兴奋的，未被探索的生物学领域。其中许多修饰直接来自中枢代谢物， 从而将它们与细胞的代谢状态紧密地联系在一起。主题2.大系统和多组学 探讨生理学和新陈代谢的分析。人类基因组测序，一个分水岭时刻 对于生物学，建立一个深入了解基因及其功能的框架。下一代测序 极大地提高了我们测量这些基因表达水平的能力，从而为我们提供了一个表面- 在一定程度上理解细胞过程在不同状态下的变化。尽管如此，无数的大型- 标度分析显示了蛋白质/RNA的边际相关性(R~0.5)，证明了对蛋白质的需求 具有同等深度和精度的测量。类似地，对脂肪和代谢物的全面分析 丰度研究表明，仅靠蛋白质表达不足以预测代谢物水平，而代谢物水平 除其他影响外，还受到蛋白质修饰和底物可用性的影响。总而言之，这些 观察结果要求开发综合的、多组学的分析，以提供更全面的 一幅生物状态的图画。