Mechanisms of translational regulation by the unfolded protein response

未折叠蛋白反应的翻译调节机制

• 批准号: 10598089
• 负责人: Smriti Sangwan
• 金额: $ 12.25万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10598089
• 关键词: Acute; Affinity; Alzheimer' s Disease; Architecture; Binding; Biological; Biology; Cell physiology; Cells; Cellular biology; Chronic; Complex; Cryoelectron Microscopy; Dedications; 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 Secretion; 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; 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

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.

项目摘要/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 采用专用机器，包括转录，联合翻译和翻译后机制 为了确保正确折叠所有蛋白质，并迅速折叠蛋白质。这 内质网（ER）是大多数跨膜蛋白和成熟的位置 分泌的蛋白质及其功能障碍与包括糖尿病在内的十几种疾病有关， 神经退行性疾病和癌症。最近的工作表明IRE1与 翻译机械。这一发现通过IRE1开辟了整个新的翻译调节领域 由其他UPR传感器。在此提案中，我将以这种新发现的模式获得高分辨率见解 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的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有毒构象状态。我 通过在实验室中使用细胞生物学方法，继续在蛋白质折叠领域进行训练 UCSF的彼得·沃尔特博士。我将通过学习最新技术来继续我的专业发展 冷冻和功能基因组学。在戴维·阿加德（David Agard）博士的精神状态下，该方法的先驱 单粒子冷冻，彼得·沃尔特（Peter Walter）博士，UPR和IRE1生物学领域的专家，与顾问和 功能基因组专家Stephen Flod博士的指导，我将获得重大培训，最终将 帮助我过渡到独立的研究职业。 职业目标：我的职业目标是建立一个研究计划，调查 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，该机构的员工为 特定基因的微调翻译，以防止压倒蛋白质折叠机械以及细胞如何 正确地构建蛋白质聚集体是我在独立中要解决的一些问题 研究。