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.

项目总结/摘要 研究项目概述：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 以确保所有的蛋白质都正确折叠，而不正确折叠的蛋白质被快速分类。的 内质网（ER）是大多数跨膜蛋白折叠和成熟的场所， 分泌的蛋白质，它的功能障碍与十几种不同的疾病有关，包括糖尿病， 神经退行性疾病和癌症。最近的研究表明，IRE 1在物理上与 翻译机器这一发现为IRE 1的翻译调控开辟了一个全新的领域， 其他的UPR传感器。在这个建议中，我将在这个新发现的模式中获得高分辨率的见解， ER的翻译调控。 职业发展计划和环境：作为加州大学洛杉矶分校大卫艾森伯格实验室的一名研究生，我 利用X射线晶体学研究了蛋白质聚集途径中的毒性构象状态。我 我继续在蛋白质折叠领域的训练，在实验室里采用细胞生物学的方法 彼得·沃尔特博士的照片我将继续我的专业发展，学习最新的技术， CryoEM和功能基因组学。在大卫阿加德博士的指导下， Peter Walter博士是UPR和IRE 1生物学领域的专家， 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 帮助我过渡到独立的研究生涯。 职业目标：我的职业目标是建立一个研究项目，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， 微调特定基因的翻译，以防止压倒性的蛋白质折叠机制和细胞如何 正确的蛋白质聚合物的慢性积累是我将在我的独立演讲中解决的一些问题。 research.