Regulatory Role of Splicing In Inflammation

剪接在炎症中的调节作用

• 批准号: 9169519
• 负责人: DAVID BALTIMORE
• 金额: $ 28.75万
• 依托单位: CALIFORNIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9169519
• 关键词: Address; Appearance; Attention; Autoimmune Process; Autoimmunity; Behavior; Biological; Biological Testing; Cell Line; Cells; Chronic; Clustered Regularly Interspaced Short Palindromic Repeats; Consensus; Data; Development; Event; Exons; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Health; Heart Diseases; Immune; Immune system; Infection; Inflammation; Inflammatory; Inflammatory Response; Introns; Kinetics; Logic; Malignant Neoplasms; Measures; Messenger RNA; Methods; Molecular Profiling; Mus; Physiological; Play; Property; Proteins; RNA; RNA Splicing; Reading; Reagent; Regulation; Reporter; Role; Specificity; Stimulus; System; Techniques; Technology; Testing; Therapeutic Intervention; Time; Transcript; Work; base; cell type; exosome; fighting; improved; interest; knockin animal; mRNA Precursor; mRNA Transcript Degradation; next generation sequencing; pathogen; repaired; research study; tissue culture; transcription factor; transcriptome sequencing

PROJECT SUMMARY Regulation of inflammation is of crucial importance, both for the advancement of therapeutic intervention and for the limiting of deleterious autoimmune complications. The precise tuning of the inflammatory response involves transcription and, from our recent unpublished studies, meticulous regulation of hundreds of mRNAs at many levels. Since we discovered NF-κB in 1986, we have been examining a variety of properties of this transcription factor system, focusing most of our attention on the role of NF-κB in the immune system, particularly in orchestrating the inflammatory response to pathogen challenge. In recent years, we have studied the regulatory events underpinning the precise timing of gene expression during the inflammatory response. We used RNA-seq to target only inflammatory transcripts and have quantified splicing kinetics of introns of inflammatory genes, finding that some are orders of magnitude slower to splice than expected. We find that they confer a significant reduction in gene expression as delays in splicing are often concomitant with RNA exosome engagement. We predict this may be a regulatory mechanism, and call them ‘bottleneck introns.’ In this proposal, we propose to test the biological relevance of bottleneck introns in tissue culture and by making mice (Aim 1) to see if limits to inflammation are altered in the context of a repaired intron. In addition, we propose to investigate whether there are biological contexts (stimulus, cell-type, developmental state) that confers improved splicing of a bottleneck (Aim 2), therefore providing a regulatory framework for this finding.

项目总结