National Center for Quantitative Biology of Complex Systems

项目总结-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技术做出新的，有影响力的发现 技术.最初，我们的TR& D受到广泛的新陈代谢领域对新药物的明确需求的影响。 可以加速发现的技术。利用我们在这一领域的专长，我们招募了世界级的科学家 他们设计了一些项目，作为我们TR& D的强大测试平台。其中许多项目已被驱动， 完成，而其他人仍然活跃，并影响了新的TR& D。这些互动-以及 我们的技术的广泛应用-导致我们的重点领域的自然扩展。我们也成为 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。对于周期2，两个总体DBP主题激励我们的资源的技术 发展：主题1。新的代谢产物衍生的翻译后修饰（PTM）。PTM的能力 例如磷酸化和泛素化来调节信号传导和蛋白质周转， 我们通过最初的DBPs加速了这一领域的发现。现在，科学界 经历了一个兴趣的复兴，在研究不足的修饰如何发挥控制蛋白质功能， 不同的细胞生物学背景。这些包括甲基化、酰化、糖基化和羟基化。 此外，对其他生物物种的修饰，如糖基化核酸，正在出现， 令人兴奋的未被探索的生物学领域。这些修饰中的许多直接源自中心代谢物， 从而将它们与细胞的代谢状态紧密联系起来。主题2.大规模系统和多组学 分析以探索生理学和新陈代谢。人类基因组测序，一个分水岭 对于生物学，为深入了解基因及其功能建立了一个框架。下一代测序 大大提高了我们测量这些基因表达水平的能力，从而给了我们一个表面- 了解细胞过程如何在对比状态下发生变化。尽管如此，无数的大- 规模分析揭示了边际蛋白质/RNA相关性（R ~ 0.5），表明需要蛋白质 深度和精度相当的测量。同样，脂质和代谢物的综合分析 丰度揭示了蛋白质表达本身不足以预测代谢物水平， 还受到蛋白质修饰和底物可用性等因素的影响。总的来说，这些 观测要求发展综合的、多组学的分析， 这是一个生物状态的图像。

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.