National Center for Dynamic Interactome Research

描述（由申请人提供）：生命的涌现特性需要大分子的动态相互作用，其中两大类是蛋白质和核酸。这些相互作用形成了塑造细胞、传递信息和控制细胞行为的大分子机器和动态联系，而分子相互作用网络（相互作用组）中的致病性改变是疾病的基础。因此，我们对生物系统及其病理的理解和调节依赖于阐明和解释这些相互作用及其动力学的能力。对于核酸来说，最近的进展导致了基因组数据的爆炸式增长。然而，蛋白质在丰度和性质上的多样性令人难以置信，这使得它们在执行动态任务时具有高度的通用性，但同时也非常难以分析。正是由于这些原因，相互作用革命仍然远远落后于基因组革命。拟议中的国家动态相互作用组研究中心（NCDIR）将细胞生物学实验室、一个已建立的质谱资源、一个系统生物学资源和一个计算结构生物学中心结合起来。NCDIR的目标是协同开拓新的和改进的方法，将这些技术整合到一个基本新颖的“管道”方法中，以满足生物医学界对能够快速、可靠和常规地识别和表征动态细胞相互作用组的技术的迫切需求。我们将从开发纯化和保存技术开始，以高保真度，围绕任何选定的大分子的相互作用体的各种定义形式的分层排列。然后，我们将为动态复合体提供全面、高度定量、详细的时间和结构数据。这些数据将用于生成可预测的、可测试的、可操作的结构和机制模型，并指导实验将重点放在那些最有信息的模型上。这些模型旨在为生物医学界提供合理的靶向干预手段和药物设计策略。这些方法将通过一组选定的驱动生物项目和合作项目进行开发、改进和beta测试，这些项目和合作项目可以在任何时候进入和退出我们的管道，并提出具体的技术挑战。设计国家生物医学研究所的关键是制定一个有效的培训和传播方案，以满足生物医学界的迫切需要。

DESCRIPTION (provided by applicant): The emergent properties of life require the dynamic interactions of macromolecules, the two major classes of which are proteins and nucleic acids. These interactions form macromolecular machines and dynamic liaisons that shape the cell, transmit information and control cellular behaviors, and pathogenic alterations in molecular interaction networks (interactomes) underlie disease. Our understanding and modulation of biological systems, as well as their pathologies, thus relies on the ability to elucidate and interpret these interactions and their dynamics. For nucleic acids, recent advances have led to an explosion of genomic data. However, proteins are incredibly diverse in their abundance and their properties, making them highly versatile for their dynamic tasks, but at the same time exceptionally difficult to analyze. It is for these reasons that the interactomic revolution still ags very far behind the genomic revolution. The proposed National Center for Dynamic Interactome Research (NCDIR) couples cell biology laboratories, an established mass spectrometry resource, a systems biology resource, and a computational structural biology center. The goal of the NCDIR is to synergistically pioneer new and improved approaches, integrating these technologies into a fundamentally novel "pipeline" approach to address the urgent need of the biomedical community for technologies that can rapidly, reliably and routinely identify and characterize the dynamic cellular interactome. We will begin by developing technologies for purifying and preserving, with high fidelity, various defined forms of the hierarchical arrangement of interactors surrounding any chosen macromolecule. We will then provide comprehensive, highly quantitative, detailed temporal and structural data for dynamic complexes. Such data will be used to generate structural and mechanistic models that are predictive, testable, actionable, and guide experiments to focus on those that are most informative. The models aim to provide the biomedical community with the means for rational target-based intervention and drug design strategies. These approaches will be developed, refined and beta-tested via a selected set of Driving Biological Projects and Collaborations that can enter and exit our pipeline at any point, and which present specific technological challenges. Critical to the design of the NCDIR is an effective training and dissemination program that is responsive to the urgent needs of the biomedical community.