EAGER: Engineering Molecular Sensors Of Endoplasmic Reticulum-Associated Degradation (ERAD)

这项由生物技术、生化和生物质工程项目颁发的NSF奖支持开发新工具，这些工具将帮助研究人员发现细胞加工的错误折叠蛋白质的降解剂。错误折叠蛋白的降解在生物加工和医学上都是重要的，因为某些重组治疗性蛋白表达的最大问题之一是这些蛋白在细胞内的聚集。作为分泌目标的蛋白质在细胞内以聚集或错误折叠的蛋白质形式积累，会导致细胞应激，最终通过细胞凋亡导致细胞死亡，导致生物处理应用中的生产力损失。在阿尔茨海默氏症或帕金森氏症等疾病中，聚集蛋白的存在似乎会导致神经退化。在蛋白质错误折叠疾病中，内质网或内质网应激可能在细胞死亡中发挥作用。加强导致这些蛋白质降解的机制可能会减缓疾病的进展。在这个项目中，研究人员提议开发一种新的基于荧光的分析方法，用于检测特定蛋白质降解途径(内质网降解)的激活。这项测试是能够开发高通量筛选分子的第一步，这些分子将促进错误折叠蛋白质的细胞内降解。该检测方法将在生物加工业和生物医学中得到应用。该研究所将整合研究生和本科生的研究和教育，并致力于增加生物技术领域的多样性。

This NSF award by the Biotechnology, Biochemical and Biomass Engineering program supports the development of novel tools that will aid researchers in the discovery of enhancers of degradation of misfolded proteins that are processed by cells. The degradation of misfolded proteins is important both in bioprocessing and in medicine, as one of the biggest problems in expression of certain recombinant therapeutic proteins is the intracellular aggregation of these proteins. Proteins which are targeted for secretion that accumulate as aggregated or misfolded proteins inside cells cause cellular stress and eventually cell death via apoptosis, leading to loss of productivity in bioprocessing applications. In diseases such as Alzheimer's or Parkinson's, the presence of an aggregated protein appears to lead to neurodegeneration. In protein misfolding diseases, endoplasmic reticulum or ER stress may play a role in cell death. The enhancement of mechanisms which would lead to degradation of those proteins might slow down the progression of disease. In this project, the investigators propose to develop a novel fluorescence based assay for the detection of the activation of a specific protein degradation pathway (ER-degradation). This assay is the first step in being able to develop high throughput screens for molecules that will enhance intracellular degradation of misfolded proteins. The assay will have applications both in the bioprocessing industry and in biomedicine. The PI will integrate research and education at the graduate and undergraduate levels, and work to increase the diversity of the biotechnology field.