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The Role of RNA Binding Motif 5 in Traumatic Brain Injury

RNA 结合基序 5 在创伤性脑损伤中的作用

基本信息

批准号：
9494899
负责人：
TRAVIS C JACKSON
金额：
$ 34.23万
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：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9494899
关键词：
Apoptosis Autophagocytosis Axon Binding Brain Cardiovascular Diseases Caspase Cause of Death Cell Death Cells Cerebral Ischemia Cessation of life Cognitive Data Disease Down-Regulation Enterobacteria phage P1 Cre recombinase Etiology Event Exons Foundations Funding Future Gene Deletion Gene Expression Genes Hippocampus (Brain)Histologic Human Impairment In Vitro Injury Knock-out Knockout Mice Knowledge Learning Location Malignant Neoplasms Measures Mechanics Mediating Medical Memory Messenger RNA Modeling Molecular Monomeric GTP-Binding Proteins Motor Multiple Trauma Mus Nervous System Trauma Neurologic Neuronal Injury Neurons Normal Cell Nuclear Organ Outcome Pathologic Play Predisposition Proteins Publishing RBM5 gene RNA Binding RNA Splicing RNA analysis RNA-Binding Proteins Rattus Reporting Research Research Activity Resource Sharing Resources Role Signal Transduction Spinal Cord Spinal cord injury Staurosporine Stretching Subfamily lentivirinae Testing Time Tissues Toxic effect Trauma Traumatic Brain Injury United States National Institutes of Health Up-Regulation Vertebral column Work behavioral outcome cancer cell cell growth central nervous system injury clinically relevant cognitive function controlled cortical impact data resource disability drug development experimental study gene function improved in vitro testing in vivo in vivo evaluation innovation knock-down mutant nervous system disorder neurological recovery neuron loss neuropathology neuroprotection neurotoxic neurotoxicity next generation sequencing novel novel therapeutic intervention novel therapeutics overexpression prevent repaired small molecule tool transcriptome treatment strategy

项目摘要

ABSTRACT Traumatic brain injury (TBI) is a leading cause of death and disability in the young. Treatments are desperately needed to prevent cell death, repair neuronal connectivity, and improve cognitive outcomes after a TBI. This project will test if gene deletion of RNA binding motif 5 (RBM5) in mice improves molecular and histological readouts and behavioral outcomes after a controlled cortical impact (CCI) injury. RNA binding proteins (RBPs) regulate all aspects of mRNA (e.g. RNA splicing, gene expression, stability, and cellular localization). In recent years a number of RBPs have been associated with the etiology of disorders ranging from cancer, to cardiovascular and neurological disease. RBM5 is a pro-death RBP. The mechanisms by which RBM5 induces cell death involves upregulation of pro-death genes and also via the modulation of mRNA splicing ,which gives rise to toxic proteins with increased potency. Forced overexpression of RBM5 in cancer cells causes apoptosis, autophagy, and impedes cell growth. Very little is known about the function(s) of RBM5 in non-cancerous (i.e. normal) cells and tissues. Germane to the CNS, we showed that RBM5 levels increase after a TBI in mice. Independent of our work, RBM5 levels also reportedly increase after a traumatic spinal cord injury. It remains to be elucidated if RBM5 activates cell death in primary CNS cells (as it does in cancer). Our new preliminary data show that RBM5 overexpression in primary rat cortical neurons increases their susceptibility to a subsequent mechanical stretch-injury. This new finding is in line with our hypothesis that (1) RBM5 inhibition is a promising new therapeutic strategy for the treatment of CNS injury, and (2) suggests that RBM5 dysregulation may mediate pathological changes in gene expression which has been observed to occur after a TBI. In this project we will definitely test if RBM5 inhibition is neuroprotective in vivo. Novel conditional RBM5 KO mice will be subjected to a CCI induced injury. Neuropathology in WT versus KOs will be examined 1-21d post-injury. Also, learning and memory function will be examined 14-21d post-injury. Additionally we will analyze changes in global gene expression/splicing in primary cortical neurons after a mechanical stretch- injury, and also in which RBM5 levels are manipulated (i.e. by lentivirus mediated knockdown vs. overexpression). This study represents the most in-depth, largest, and only analysis of RBM5 gene function in brain which has been done to date.

摘要