Regulation of the ER-associated Degradation by Importin Beta

智力上的优点。内质网(ER)是一个大的膜结合囊，用于在细胞中产生许多蛋白质。然而，很大一部分蛋白质在生产过程中或由于病原性侮辱，如暴露在有毒物质或基因突变中而出现缺陷。为了解决这个问题，细胞进化了一种内质网蛋白质质量控制系统来识别这些缺陷蛋白质，并从内质网中提取它们进行破坏。当质量控制过程不能正常运作时，有缺陷的蛋白质会在内质网中积聚，严重时会导致细胞损伤，甚至细胞死亡。因此，如何将有缺陷的蛋白质从内质网中移除是一个基本的生物学问题，但不幸的是，人们仍然知之甚少。这个项目将研究在这个实验室中发现的一种意想不到的物理和功能相互作用，在Importin beta和ER蛋白质质量控制系统中的一组其他蛋白质之间。Importin beta因其将蛋白质运入和运出细胞核的功能而广为人知。这项研究将确立Importin beta在ER蛋白质质量控制中的新角色，从而为这一重要过程的整体调控提供新的见解。这个项目将涉及高中生、高中理科教师、博士后研究员和博士生。参与这项研究的学员将学习一种综合的方法，使用包括分子生物学、生物化学和细胞生物学在内的跨学科方法来实现Importin的新型ER蛋白质质量控制功能。为了培养学员的高科学成就，将制定一份问卷，以评估他们所学到的基本知识和技能。这些信息还将有助于确定培训方面的关键需求，这些需求将纳入实验室未来受训人员的指导计划。该计划将利用与当地高中科学计划建立的伙伴关系，扩大代表不足的受训人员的参与。参与这个项目的科学教师将帮助招募学生参加这个项目，并通过这些经验激励班上的其他学生。将制定计划，促进与其他机构实验室的合作，分享研究成果和资源，并加强外联和培训机会。这项研究的广泛传播将通过鼓励受训人员在科学会议上介绍他们的工作以及通过因特网分发电子教材来实现。

Intellectual merit. The endoplasmic reticulum (ER) is a large membrane-bound sac for the production of many proteins in cells. However, a significant fraction of the proteins become defective during production or due to pathogenic insults, such as exposure to toxic agents or genetic mutations. To deal with this problem, cells have evolved an ER protein quality control system to recognize those defective proteins and extract them from the ER for destruction. When the quality control process does not function properly, defective proteins build up in the ER, which in severe cases can lead to cell damage and even cell death. Therefore, how defective proteins are removed from the ER is a fundamental biological problem, but unfortunately remains poorly understood. This project will investigate an unexpected physical and functional interaction, discovered in this laboratory, between importin beta and a group of other proteins in the ER protein quality control system. Importin beta is well known for its function in transporting proteins in and out of the nucleus. The research will establish a new role for importin beta in ER protein quality control and thus will provide new insights into the overall regulation of this important process.Broader impacts. This project will involve high school students, high school science teachers, a postdoctoral fellow, and a PhD student. Trainees involved in this research will learn an integrative approach to the novel ER protein quality control function of importin Ò using interdisciplinary approaches, which will include molecular biology, biochemistry, and cell biology. To foster high scientific achievement of trainees, a questionnaire will be developed to assess the basic knowledge and skills they learn. This information will also help to identify critical needs in training that will be incorporated into the mentoring plans for future trainees in the laboratory. The program will utilize established partnerships with local high school science programs to broaden the participation of underrepresented trainees. Science teachers involved in this project will help to recruit students for this project and through these experiences will inspire other students in their classes. Plans will be undertaken to foster collaborations with laboratories at other institutions to share research results and resources and to enhance outreach and training opportunities. Broad dissemination of this research will be achieved by encouraging trainees to present their work at scientific conferences and by distributing electronic educational materials through the Internet.