Mechanisms of translational regulation by the unfolded protein response

未折叠蛋白反应的翻译调节机制

基本信息

批准号：
10449925
负责人：
Smriti Sangwan
金额：
$ 10万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10449925
关键词：
Acute Address Affinity Alzheimer&apos s Disease Architecture Biological Biology Cell physiology Cells Cellular biology Chronic Complex Cryoelectron Microscopy Defect Development Development Plans Diabetes Mellitus Disease Electron Microscopy Facility Endoplasmic Reticulum Ensure Environment Enzymes Floor Functional disorder Genes Genetic Transcription Goals Health In Vitro Inositol Integral Membrane Protein Learning Link Malignant Neoplasms Mammalian Cell Measures Mediating Mentors Mentorship Methods Molecular Molecular Conformation Neurodegenerative Disorders Parkinson Disease Pathway interactions Patients Phase Protein translocation Protein-Serine-Threonine Kinases Proteins Quality Control Research Research Project Summaries Resolution Ribosomes Role Signal Recognition Particle Signal Transduction Site Stress Techniques Therapeutic Training Transcriptional Regulation Translating Translational Regulation Translations Triage Work X-Ray Crystallography aggregation pathway base brain tissue career career development endoplasmic reticulum stress experimental study functional genomics graduate student in vivo insight macromolecular assembly misfolded protein particle post-doctoral training prevent programs protein aggregation protein folding protein misfolding proteostasis response ribosome profiling sensor structural biology therapeutic target

项目摘要

Project Summary/Abstract Summary of Research Project: Protein folding is one of the most critical nodes of cellular health and cells employ dedicated machineries comprised of transcriptional, co-translational and post-translational mechanisms to ensure all proteins are correctly folded and the incorrectly folded proteins are rapidly triaged. The endoplasmic reticulum (ER) is the site of folding and maturation of the majority of transmembrane proteins and secreted proteins, and its dysfunction is linked to a dozen different diseases including diabetes, neurodegenerative diseases and cancer. Recent work suggests that IRE1 is physically linked to the translational machinery. This finding opens an entire new field of translational regulation by IRE1 and possibly by other UPR sensors. In this proposal, I will gain high-resolution insights in this newly discovered mode of translational regulation at the ER. Career Development Plan and Environment: As a graduate student in David Eisenberg’s lab at UCLA, I investigated the toxic conformational states in the protein aggregation pathway using X-ray crystallography. I have continued my training in the field of protein folding by taking a cell biological approach working in the lab of Dr. Peter Walter at UCSF. I will continue my professional development by learning the latest techniques in CryoEM and functional genomics. Under the mentorship of Dr. David Agard, a pioneer in the methods for single-particle cryoEM, Dr. Peter Walter, an expert in the field of UPR and IRE1 biology and with advise and guidance from Dr. Stephen Floor, a functional genomics expert, I will gain significant training that will ultimately help me transition to an independent research career. Career Goals: My career goal is to establish a research program investigating the fundamental mechanisms of protein folding in cells. How cells manage partially folded and misfolded proteins, the mechanism employed to fine-tune translation of specific genes to prevent overwhelming the protein folding machinery and how cells correct chronic build-up of protein aggregates are some of the questions that I will address in my independent research.

项目概要/摘要研究项目摘要：蛋白质折叠是细胞健康和细胞最关键的节点之一采用由转录、共翻译和翻译后机制组成的专用机制确保所有蛋白质都正确折叠，并且快速分类错误折叠的蛋白质。内质网 (ER) 是大多数跨膜蛋白折叠和成熟的场所分泌蛋白，其功能障碍与包括糖尿病在内的十几种不同疾病有关，最近的研究表明 IRE1 与神经退行性疾病和癌症有物理联系。这一发现开辟了 IRE1 的翻译调控的全新领域。在这个提案中，我将获得这种新发现的模式的高分辨率见解。 ER 的翻译调节。职业发展计划和环境：作为加州大学洛杉矶分校 David Eisenberg 实验室的研究生，我使用 X 射线晶体学研究了蛋白质聚集途径中的毒性构象状态。通过在实验室工作的细胞生物学方法继续我在蛋白质折叠领域的培训我将通过学习最新的技术来继续我的专业发展。在冷冻电镜和功能基因组学方法先驱 David Agard 博士的指导下。单颗粒冷冻电镜，Peter Walter 博士是 UPR 和 IRE1 生物学领域的专家，并提供建议和帮助在功能基因组学专家 Stephen Floor 博士的指导下，我将获得重要的培训，最终将帮助我过渡到独立研究职业。职业目标：我的职业目标是建立一个研究项目，调查基本机制细胞中的蛋白质折叠。细胞如何管理部分折叠和错误折叠的蛋白质，其机制微调特定基因的翻译，以防止压倒蛋白质折叠机制以及细胞如何正确的蛋白质聚集体的长期积累是我将在我的独立文章中解决的一些问题研究。