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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.

项目总结/文摘