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：
10200911
负责人：
TRAVIS C JACKSON
金额：
$ 32.7万
依托单位：
UNIVERSITY OF SOUTH FLORIDA
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 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10200911
关键词：
3-Dimensional 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 Lentivirus 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 Structure TBI treatment 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.

抽象的创伤性脑损伤（TBI）是年轻人死亡和残疾的主要原因。治疗是迫切需要防止细胞死亡，修复神经元连通性并改善认知结果 TBI。该项目将测试小鼠RNA结合基序5（RBM5）的基因缺失是否可以改善分子和受控皮质影响（CCI）损伤后的组织学读数和行为结果。 RNA结合蛋白（RBP）调节mRNA的所有方面（例如RNA剪接，基因表达，，稳定性和细胞定位）。近年来，许多RBP与从癌症到心血管和神经系统疾病的疾病。 RBM5是亲死亡的RBP。这 RBM5诱导细胞死亡的机制涉及促血统基因的上调以及通过 mRNA剪接的调节，这会导致效力增加的有毒蛋白。强迫过表达癌细胞中的RBM5的凋亡，自噬并阻碍细胞生长。关于 RBM5的功能在非癌性（即正常）细胞和组织中。与中枢神经系统的理查者，我们表明小鼠TBI后RBM5水平升高。独立于我们的工作，据报道，RBM5水平也会在创伤性脊髓损伤。如果RBM5激活原代CNS细胞中的细胞死亡（AS）它在癌症中确实如此）。我们的新初步数据表明，原发性大鼠皮质神经元中的RBM5过表达增加了对随后的机械伸展伤的敏感性。这个新发现符合我们的假设（1）RBM5抑制是一种有希望的新治疗策略，用于治疗中枢神经系统损伤，（2）表明RBM5失调可能介导基因表达的病理变化观察到在TBI之后发生。在这个项目中，我们一定会测试RBM5抑制在体内是否具有神经保护作用。新颖的条件 RBM5 KO小鼠将遭受CCI诱导的损伤。将检查WT与KOS中的神经病理学 1-21D伤亡后。此外，将检查学习和记忆功能14-21D伤害后。另外，我们会的分析机械拉伸后，原发质神经元中全球基因表达/剪接的变化 - 受伤，以及在其中操纵RBM5水平（即慢病毒介导的敲低与过表达）。这项研究代表了RBM5基因功能最深入，最大，唯一的分析迄今为止已经完成的大脑。