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Collaborative Research: Integrating Theory and Experiment to Unravel Protein Transport in the ER

合作研究：结合理论和实验来解开内质网中的蛋白质转运

基本信息

批准号：
2034482
负责人：
Elena Koslover
金额：
$ 55.18万
依托单位：
University of California-San Diego
依托单位国家：
美国
项目类别：
Standard Grant
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-15 至 2024-12-31
项目状态：
已结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=2034482&HistoricalAwards=false
关键词：
Collaborative Research Integrating Theory Experiment

项目摘要

The endoplasmic reticulum, or ER, is a specialized intracellular structure responsible for a myriad of critical cellular functions, including protein synthesis, quality-control, and export. It is estimated that about one third of all mammalian proteins are created and then exported from the ER as the first step on their way to being secreted from the cell to become the signal carriers and receptors that interface with the extracellular world. The ER itself forms an interconnected network of sheets and hollow tubules that hosts a variety of protein processing pathways. This project aims to address a fundamental question in cell biology -- how does the structural complexity of the ER regulate and support its functional role as the protein processing hub of the cell? An interdisciplinary approach combines imaging within live cells, predictive physical modeling, and state-of-the-art simulation and data-analysis techniques to explore how proteins navigate through the ER maze. This collaborative effort seeks to unravel how the unique physical structure of the ER regulates its critical biological functions of protein sorting and export. The Broader Impacts of this work includes the intrinsic merit of the research as all eukaryotic cells have ER and dysfunctions of this organelles have been implicated in such human afflictions as diabetes and Parkinson’s disease. Additionally, the work will be integrated with a broad interdisciplinary educational program that spans from an elementary school science club, to a high school robotics team, to undergraduate research interns, aiming to introduce students at all educational levels to the insights that may be gained by applying physical and mathematical approaches to biological problems.The endoplasmic reticulum forms a continuous polymorphic network of stacked sheets and hollow tubules that spans throughout the intracellular space and is responsible for the folding, quality-control, sorting, and export of secreted proteins. The primary goal of this project is to establish a structure-function relationship for this organelle, developing a quantitative understanding of how its unique morphology supports its role as a protein delivery network. This goal will be approached collaboratively from the dual perspectives of physical model-building and dynamic live-cell imaging. A mathematical framework will be developed that combines analytical results for reaction-diffusion processes in complex geometries with novel simulation techniques to establish how network morphology modulates the kinetics of proteins finding binding partners, sorting regions, and exit sites within the network. Rapid confocal imaging of ER structure and photoactivated luminal and membrane proteins will enable quantification of the underlying dynamics of network structures (including tubule junctions and exit sites) and the embedded proteins. Genetic and pharmacological perturbations will be leveraged to test predictions of the effect of structure on intra-ER protein transport. The efficiency of protein sorting and export from the ER will be quantified using a synchronized accumulation-and-release system, and the contribution of physical factors such as bulk luminal flow and exit site distribution will be explored through a confluence of theoretical models and live-cell measurements. Ultimately, a feedback loop between theory and experiment will elucidate the underlying principles that link the complex architecture of the ER with its crucial protein processing functions.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

内质网是一种特殊的细胞内结构，负责多种关键的细胞功能，包括蛋白质合成、质量控制和输出。据估计，大约三分之一的哺乳动物蛋白质是由内质网制造出来的，然后从内质网输出，这是它们从细胞分泌出来的第一步，成为与细胞外世界接触的信号载体和受体。内质网本身形成一个由薄片和中空小管组成的相互连接的网络，承载着各种蛋白质加工途径。该项目旨在解决细胞生物学中的一个基本问题——内质网的结构复杂性如何调节和支持其作为细胞蛋白质加工中心的功能作用？跨学科的方法结合了活细胞内的成像，预测物理建模，以及最先进的模拟和数据分析技术，以探索蛋白质如何在ER迷宫中导航。这项合作努力旨在揭示内质网独特的物理结构如何调节其蛋白质分类和输出的关键生物学功能。这项工作的广泛影响包括研究的内在价值，因为所有真核细胞都有内质网，这种细胞器的功能障碍与糖尿病和帕金森病等人类疾病有关。此外，这项工作将与一个广泛的跨学科教育项目相结合，从小学科学俱乐部到高中机器人团队，再到本科研究实习生，旨在向所有教育水平的学生介绍通过应用物理和数学方法解决生物问题可能获得的见解。内质网形成一个连续的多态网络，由堆叠的薄片和中空的小管组成，横跨整个细胞内空间，负责折叠、质量控制、分类和分泌蛋白质的输出。该项目的主要目标是建立这种细胞器的结构-功能关系，对其独特的形态如何支持其作为蛋白质递送网络的作用进行定量理解。这一目标将从物理模型构建和动态活细胞成像的双重角度来合作实现。将开发一个数学框架，将复杂几何结构中反应扩散过程的分析结果与新颖的模拟技术相结合，以确定网络形态如何调节蛋白质在网络中寻找结合伙伴、分类区域和退出位点的动力学。内质网结构和光激活的管腔和膜蛋白的快速共聚焦成像将使网络结构（包括小管连接和出口位点）和嵌入蛋白的潜在动力学量化成为可能。遗传和药理学扰动将被用来测试结构对内质网内蛋白质运输影响的预测。蛋白质从内质网分选和输出的效率将使用同步积累和释放系统进行量化，并且将通过理论模型和活细胞测量的融合来探索物理因素（如大量腔流和出口位点分布）的贡献。最终，理论和实验之间的反馈回路将阐明将内质网的复杂结构与其关键的蛋白质加工功能联系起来的基本原理。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Mitochondrial mRNA localization is governed by translation kinetics and spatial transport.

线粒体mRNA定位由翻译动力学和空间运输控制。

DOI：
10.1371/journal.pcbi.1010413
发表时间：
2022-08
期刊：
PLoS computational biology
影响因子：
4.3
作者：
通讯作者：

Unraveling trajectories of diffusive particles on networks

揭示网络上扩散粒子的轨迹

DOI：
10.1103/physrevresearch.4.023182
发表时间：
2022
期刊：
Physical Review Research
影响因子：
4.2
作者：
Sun, Yunhao;Yu, Zexi;Obara, Christopher J.;Mittal, Keshav;Lippincott-Schwartz, Jennifer;Koslover, Elena F.
通讯作者：
Koslover, Elena F.

Endoplasmic reticulum network heterogeneity guides diffusive transport and kinetics