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The mRNA splicing factor RBM5: A new therapeutic target for TBI

mRNA剪接因子RBM5：TBI的新治疗靶点

基本信息

批准号：
8749903
负责人：
TRAVIS C JACKSON
金额：
$ 19.22万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8749903
关键词：
Acute Brain Injuries Anthraquinones Apoptotic Applications Grants Behavioral Brain Brain Diseases Brain Injuries CASP8 and FADD-like apoptosis regulating protein CASP8 gene Caspase Cause of Death Cell Death Cells Cellular Stress Cessation of life Clinical Trials Cognitive Data Drosophila pros protein Drug Targeting Enhancers Enzymes Excision Exclusion Exons Genes Hippocampus (Brain)Human Hydrogen Peroxide Impairment In Vitro Injury Intervention Introns Knowledge Learning Length Lesion Mechanics Mediating Memory Messenger RNA Modeling Mus Neurons Nuclear Nuclear Proteins Pharmaceutical Preparations Play Population Process Protein Isoforms Protein Splicing Proteins Publications RNA Binding RNA Recognition Motif RNA Splicing Rattus Recovery Reporting Role Site Spliceosome Assembly Pathway Spliceosomes Staurosporine Stretching Structure Sulfonic Acids TNF gene TNFSF10 gene TNFSF6 gene Testing Testis Therapeutic Toxic effect Transcript Traumatic Brain Injury Up-Regulation Variant Zinc Fingers cancer cell caspase-2 central nervous system injury controlled cortical impact disability in vitro testing in vivo inhibitor/antagonist injured intravenous administration mRNA Expression mRNA Precursor new therapeutic target novel overexpression pro-caspase-2 protein B protein expression public health relevance response small molecule social

项目摘要

PROJECT SUMMARY Reports estimate that over 90% of all human genes are subject to mRNA splicing. RNA splicing occurs in highly specialized structures termed nuclear spliceosomes. Spliceosomes consist of a few key proteins that catalyze the excision of target introns/exons, plus 100's of co-factors that regulate the activity/efficiency of these enzymes. Spliceosome co-factors direct many facets of splicing dynamics including distribution of different protein variants throughout the body. Brain injury and disease disturb splicing. Pathological changes in spliceosome mechanics alter splice variant expression of different survival and death proteins. An upregulation of maladaptive protein variants may exacerbate neuronal death and impair CNS recovery. RNA Binding Motif 5 (RBM5) is a splicing co-factor. It is highly expressed in the CNS and testis but its function in the healthy or injured brain is unknown. RBM5 briefly localizes to the spliceosome, very early during spliceosome assembly around pre-mRNA targets. A zinc finger domain (RanBP2-Type), and several other RNA binding domains, coordinate its highly selective interaction with spliceable exons in pre-mRNA targets. In cancer cells, RBM5 regulates splice variant selection of caspase-2 (pro-death) and c-FLIP (pro-survival) genes. It promotes the exclusion of exon 9 from caspase-2, and exon 7 from c-FLIP mRNA. This induces caspase2L and c-FLIPL protein expression, respectively. Caspase2L is a pro-death splice variant. The c-FLIPL splice variant also has pro-apoptotic functions. In contrast, RBM5 inhibition causes exon 9/7 retention, respectively, and forces caspase-2s/c-FLIPs expression. Caspase-2s and c-FLIPs are both potent pro-survival variants. Thus RBM5 promotes cell death by upregulating the ratio of pro-death to pro-survival splice variants. RBM5 has not been studied in the brain. High expression in the CNS suggests that it may play a key role in splicing-mediated cell death mechanisms. To the best of our knowledge, no drug has ever been developed to specifically target pro-death splicing mechanisms in the brain - thus the therapeutic value of splicing directed therapies is completely unknown. Our preliminary data show that RBM5 is highly enriched in the hippocampal CA3 formation - a neuron population that is especially vulnerable to traumatic brain injury (TBI). Furthermore, we show that anthraquinone-2-sulfonic acid (AQ2S), the world's first small-molecule RBM5 inhibitor (that blocks the RanBP2-Type domain), decreases neuronal death after TBI in vitro and in vivo. This grant proposal seeks to test our hypothesis that RBM5 is a potent pro-death splicing factor in rat/human neurons (i.e. show that it upregulates caspase-2L and c-FLIPL splicing in these cells), and further confirm our preliminary data showing that AQ2S is the first viable drug to block pro-death splicing mechanisms in the brain.

项目总结