Translational Control by Osmotically Active Solutes

渗透活性溶质的转化控制

基本信息

批准号：
9908062
负责人：
MARIA HATZOGLOU
金额：
$ 58.24万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-15 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9908062
关键词：
Address Amino Acyl-tRNA Synthetases Apoptosis Apoptotic Attenuated Autophagocytosis Award Biochemical Bioinformatics Cell Cycle Progression Cell Nucleus Cell membrane Cells Cellular Stress Cessation of life Chronic Complex Cross-Linking Reagents Cysteine Cytoplasm Data Diabetes Mellitus Disease Electron Transport Complex III Endoplasmic Reticulum Epithelial Cells Evaluation Exposure to Genes Genetic Translation Genomics Grant High Pressure Liquid Chromatography IKKepsilon Immunoprecipitation In Vitro Inflammation Inflammatory Inflammatory Response Knock-in Malignant Neoplasms Manuscripts Measurement Mediating Membrane Membrane Proteins Messenger RNA Methodology Modification Mutation NADPH Oxidase NF-kappa B Nature Nerve Degeneration Nutritional Obesity Oxidative Stress Pathology Pathway interactions Phosphorylation Physiological Polyribosomes Post-Translational Protein Processing Protein Biosynthesis Proteins Proteomics Prothrombin Publishing RNA RNA Binding Reactive Oxygen Species Recombinants Recovery Regulation Ribosomes Role Science Signal Pathway Signal Transduction Small Nucleolar RNA Stress Symptoms Testing Therapeutic Time Transcriptional Regulation Transfer RNA Aminoacylation Translating Translations cell type corneal epithelium crosslink desensitization detection of nutrient endoplasmic reticulum stress follow-up genome-wide human disease in vitro activity intestinal epithelium mutant novel oxidation p65 polysome profiling protein complex reconstitution response solute trafficking transcriptome sequencing

Address Amino Acyl-tRNA Synthetases Apoptosis Apoptotic Attenuated Autophagocytosis Award Biochemical Bioinformatics Cell Cycle Progression Cell Nucleus Cell membrane Cells Cellular Stress Cessation of life Chronic Complex Cross-Linking Reagents Cysteine Cytoplasm Data Diabetes Mellitus Disease Electron Transport Complex III Endoplasmic Reticulum Epithelial Cells Evaluation Exposure to Genes Genetic Translation Genomics Grant High Pressure Liquid Chromatography IKKepsilon Immunoprecipitation In Vitro Inflammation Inflammatory Inflammatory Response Knock-in Malignant Neoplasms Manuscripts Measurement Mediating Membrane Membrane Proteins Messenger RNA Methodology Modification Mutation NADPH Oxidase NF-kappa B Nature Nerve Degeneration Nutritional Obesity Oxidative Stress Pathology Pathway interactions Phosphorylation Physiological Polyribosomes Post-Translational Protein Processing Protein Biosynthesis Proteins Proteomics Prothrombin Publishing RNA RNA Binding Reactive Oxygen Species Recombinants Recovery Regulation Ribosomes Role Science Signal Pathway Signal Transduction Small Nucleolar RNA Stress Symptoms Testing Therapeutic Time Transcriptional Regulation Transfer RNA Aminoacylation Translating Translations cell type corneal epithelium crosslink desensitization detection of nutrient endoplasmic reticulum stress follow-up genome-wide human disease in vitro activity intestinal epithelium mutant novel oxidation p65 polysome profiling protein complex reconstitution response solute trafficking transcriptome sequencing

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项目摘要

The cellular response to nutritional and environmental stress has been associated with the pathology of many diseases. Major contributors to cell fate decisions in response to stress are: (i) cell-type specific factors, (ii) time and (iii) intensity of stress. Chronic and high intensity stress conditions attenuate survival and favor apoptosis. The best-studied physiological stress conditions that are related to human disease are endoplasmic reticulum (ER) stress, which is caused by the accumulation of unfolded proteins in the ER (diabetes, obesity, cancer) and oxidative stress, which results in increased reactive oxygen species (R08) and disruption of physiological R08 Signaling (neurodegeneration). Hypeosmotic stress is less-well studied. However, the major pathology with hyperosmotic stress is induction of the inflammatory response via increased expression of NF-kB target genes. The mechanisms that control inflammation and cellular recovery from hypeosmotic stress and specifically regulation of mRNA translation are not known. Because cells activate survival and apoptotic signals in response to stress, the interplay between these competing signals is crucial for elucidating adaptation and death mechanisms. We propose to study: 1. The functions of recently discovered cytoplasmic RNA-protein complexes in the response to hyperosmotic stress 2. Test the hypothesis that oxidation of cysteines drives HnRNPA 1 out of the nucleus during hyperosmotic stress and this cytoplasmic accumulation promotes apoptosis via translational control mechanisms. 3. The mechanisms of translational control during hyperosmotic stress. We propose a novel mechanism that controls ribosomal subunit availability and function that involves induction of autophagy 4. The mechanism via which the signaling of elF2α phosphorylation inhibits adaptation and promotes inflammatory mechanisms in response to hyperosmotic cells.

细胞对营养和环境压力的反应与许多疾病的病理学。响应压力的细胞命运决定的主要贡献者是：（i）细胞类型的特定因素，（ii）时间和（iii）应力强度。慢性和高强度应力条件减弱生存并有利于凋亡。研究最佳的生理压力与人类疾病有关的疾病是内质网（ER）应力，即由ER（糖尿病，肥胖，癌症）和氧化应激，导致活性氧（R08）增加并破坏生理R08信号传导（神经变性）。倾斜应激较小的研究。但是，过度渗透应激的主要病理是诱导炎症反应通过增加NF-KB靶基因的表达。控制注射和细胞从倾斜应激中恢复，并非特别调节mRNA翻译已知。因为细胞响应应力激活生存和凋亡信号，所以相互作用在这些竞争信号之间对于阐明适应和死亡机制至关重要。我们研究的建议： 1。最近发现的细胞质RNA-蛋白复合物在反应中的功能高渗应激 2。检验以下假设：半胱氨酸的氧化使hnrnpa 1从核中驱逐出来。过度渗透应激和这种细胞质积累可通过翻译促进凋亡控制机制。 3。在过度渗透应激期间转化控制的机制。我们提出了一本小说控制核糖体亚基的可用性和功能的机制，涉及诱导自噬 4。ELF2α光磷酸化信号传导抑制适应和的机制促进对高渗细胞的响应炎症机制。