Dynamics of the cellular interactome

细胞相互作用组的动力学

基本信息

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
项目类别：
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

项目摘要

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.

细胞相互作用组的动力学：摘要；通过自然选择，蛋白质构象、相互作用及其在细胞内的动态已经被改变。经过时间的塑造，产生维持生命所需的功能。这些分子内和分子间的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景观活细胞内。因为选择过程是在拥挤的细胞内环境中进行的，所以这些细胞外不存在高度进化的相互作用组网络以及绘制和可视化它们的能力。到为了克服障碍并深入了解细胞相互作用组，我们的实验室正在开发新型体内化学交叉连接分子称为蛋白质相互作用报告 (PIR) 技术和新的质谱分析方法。这些进展为活体内相互作用组提供了初步的定量体内见解细胞。在这个项目中，我们建议进一步推进和应用蛋白质相互作用报告（PIR）技术以及质量精确测量能力的改进光谱测定阵列技术可更深入地了解细胞相互作用组。主要目标驱动我们的技术进步是为了更好地理解相互作用组动力学如何塑造功能景观细胞内。我们将解决的问题包括：多个相关细胞之间的相互作用组如何变化相关表型；药物细胞治疗如何引起影响的相互作用组动力学药理结果。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，我们将研究热和其他施加应力期间的相互作用动力学揭示哪些抑制剂诱导的相互作用组电荷对于细胞热休克反应是常见的发信号。这些努力可能揭示对目前热休克反应至关重要的相互作用组变化。限制了许多强效 Hsp90 抑制剂的效用。