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Unfolded protein response in the model species Arabidopsis thaliana

模式物种拟南芥中未折叠的蛋白质反应

基本信息

批准号：
9314588
负责人：
Federica Brandizzi
金额：
$ 31.96万
依托单位：
MICHIGAN STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-05-01 至 2020-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9314588
关键词：
Address Affect Agriculture Animal Diseases Animals Apoptosis Arabidopsis Biological Assay Biological Models Biosensor Biotechnology Candidate Disease Gene Cell Culture Techniques Cell Differentiation process Cell Line Cell Survival Cells Cellular biology Cessation of life Characteristics Collection Complement Complex Development Disease Dissection Endoplasmic Reticulum Eukaryota Eukaryotic Cell Evolution Food Gene Targeting Genes Genetic Genetic Polymorphism Genetic Transcription Genetic Variation Genets Genomics Goals Growth Growth and Development function Health Homeostasis Hormones Housekeeping Human In Vitro Individual JAM protein Knowledge Lead Learning Life Link Maps Messenger RNA MicroRNAs Modeling Molecular Molecular Analysis Molecular Chaperones Mouse-ear Cress Mutation OmpR protein Organelles Organism Output Pathway interactions Patients Pharmaceutical Preparations Phenotype Physiology Planet Earth Plant Model Plants Population Population Study Process Protein Biosynthesis Protein translocation Proteins Publishing Quantitative Trait Loci Research Resources Route Seedling Signal Pathway Signal Transduction Signal Transduction Pathway Source Stimulus Stress Study models Suppressor Mutations System Testing Transcriptional Regulation Transducers Variant Work Yeasts base biological adaptation to stress cell growth cell type combat cost design drug development endoplasmic reticulum stress food security functional genomics genetic analysis genome-wide analysis genomic tools human disease improved in vivo innovation insight loss of function misfolded protein mutant next generation sequencing novel protein folding public health relevance repaired response sensor stress management stress tolerance tool trait transcriptome

项目摘要

DESCRIPTION (provided by applicant): Protein synthesis in the endoplasmic reticulum (ER) can be dramatically upregulated under stress conditions. To avoid jamming of protein translocation and folding, the ER senses early indicators of such stress conditions and responds with the so-called unfolded protein response (UPR). This is an ancient signal transduction pathway that leads to the rapid replenishment of ER chaperones and other folding factors and avoids energy- requiring repair mechanisms before committing to apoptosis. The UPR is critical to sustain cell growth and development and to combat disease and abiotic stress. Interestingly, the efficacy of the UPR varies largely among individuals of the same species, but the underlying molecular causes are unknown. To initiate the UPR, yeast relies heavily on the action of a conserved ER stress sensor, Ire1p. During the course of evolution, the suite of UPR sensors has expanded to accommodate more specific responses in a multicellular context. The basic activation mechanisms and general function of the ER stress sensors are largely known from in vitro studies and cell culture analyses. However, how the UPR regulators work coordinately to sustain healthy cell growth and development with a minimum of energy costs is unknown. We wish to address this fundamental question in Arabidopsis thaliana, because of the conservation of plant and metazoan UPRs, the vast availability of genetic diversity and genomics resources for this model species, and the relevance of the plant kingdom as a source for renewable energy, food, and materials. The immediate goals of this proposal are 1) to define the molecular determinants underlying intra-specific UPR variability using natural populations with broad genetic diversity, 2) to understand the mechanisms that control homeostasis among the various UPR pathways in vivo, and 3) to define non-conventional mechanisms that modulate ER stress responses in intact organisms. To achieve our goals, we will pursue our genome-wide studies to characterize UPR diversity as well as our functional genomics analyses to define the mechanisms for homeostasis of the UPR signaling pathways in vivo. We will also use advanced next-generation sequencing strategies to define post-transcriptional modulation of the UPR. Our results will lead to a broad and deep understanding of the complexity of the UPR signaling network during ER stress in the context of complex multicellular organisms. Adding plants as an evolutionarily distinct and tractable model for the study of the UPR in complex organisms is also important because it will allow comparing and contrasting plant, yeast, and animal UPRs, and thus will provide significant insights into these systems, adding to the fundamental knowledge of eukaryotic cell biology at large. Our results will not only enhance our understanding of human growth and disease, they will also permit the development of drugs in a tractable multicellular model, and contribute to our knowledge of limiting factors in agricultural processes and plant biotechnology designed to sustain food security on earth.