Dynamics of the cellular interactome

细胞相互作用组的动力学

• 批准号: 10398009
• 负责人: James Edward Bruce
• 金额: $ 65.92万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10398009
• 关键词: Address; Affect; Automobile Driving; Cells; Charge; Chemicals; Chemoresistance; Crowding; Development; Environment; Goals; Heat-Shock Response; Life; Malignant Neoplasms; Maps; Mass Spectrum Analysis; Measurement; Mediating; Methods; Molecular; Natural Selections; Outcome; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phenotype; Process; Protein Conformation; Proteins; Reporter; Shapes; Signal Transduction; Stress; Technology; Time; base; crosslink; human disease; improved; in vivo; inhibitor; insight; novel

Dynamics of the cellular interactome: Abstract; Through natural selection, protein conformations, interactions and their dynamics inside cells have been shaped through time to give rise to function needed to sustain life. The set of these intra- and inter-molecular protein interactions constitute the interactome which defines fundamental functional landscapes that exists inside living cells. Because selection processes operate within the crowded intra-cellular environment, these highly evolved interactome networks and the ability to map and visualize them do not exist outside cells. To overcome barriers and gain insight on cellular interactomes, our lab is developing novel in vivo chemical cross- linking molecules referred to as Protein Interaction Reporter (PIR) technologies and new mass spectrometry methods. These developments have provided the initial quantitative in vivo insights on interactomes in live cells. In this project, we propose to further advance and apply Protein Interaction Reporter (PIR) technologies together with improvements in accurate mass measurement capabilities that are possible with mass spectrometry array technologies to gain deeper insight on the cellular interactome. The primary goal driving our technology advancement is to better understand how interactome dynamics shape functional landscapes inside cells. Questions we will address include: how are interactome changes among multiple related cellular phenotypes associated; how do cellular treatments with drugs cause interactome dynamics that affect pharmacological outcome. Finally, based on our discoveries of interactome changes with Hsp90 inhibitors that induce heat shock response, we will investigate interactome dynamics during heat and other applied stresses to reveal which if any inhibitor-induced interactome charges are common to cellular heat shock response signaling. These efforts may reveal interactome changes that are critical to heat shock response that currently limit utility of many potent Hsp90 inhibitors.

细胞互动组的动力学：摘要 通过自然选择，蛋白质在细胞内的构象、相互作用及其动力学 随着时间的推移形成的，以产生维持生命所需的功能。这些分子内和分子间集合 蛋白质相互作用构成了相互作用组，它定义了存在的基本功能图景 在活细胞内。由于选择过程在拥挤的细胞内环境中运行，这些 高度进化的相互作用组网络以及映射和可视化它们的能力不存在于细胞外。至 克服障碍，深入了解细胞相互作用，我们的实验室正在开发新的体内化学交叉 蛋白质相互作用报告(PIR)技术和新的质谱学 方法：研究方法。这些进展为活体内相互作用提供了初步的定量见解 细胞。在这个项目中，我们建议进一步发展和应用蛋白质相互作用报告(PIR)技术 同时提高了质量的精确测量能力 光谱阵列技术，以更深入地了解细胞相互作用组。首要目标驱动 我们的技术进步是为了更好地了解互动组动力学如何塑造功能景观 在牢房里。我们将解决的问题包括：多个相关细胞之间的相互作用组变化是如何 表型相关；药物的细胞治疗如何引起相互作用组动态，从而影响 药理学结果。最后，根据我们对Hsp90抑制剂相互作用组变化的发现， 诱导热休克反应，我们将研究在热和其他施加压力期间的相互作用组动力学 揭示哪些抑制剂诱导的相互作用体电荷是细胞热休克反应的共同特征 发信号。这些努力可能揭示对热休克反应至关重要的交互作用组变化，目前 限制了许多有效的Hsp90抑制剂的应用。