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Role of miR-23a/27 a in secondary injury after TBI

miR-23a/27a在TBI后继发性损伤中的作用

基本信息

批准号：
9332481
负责人：
ALAN Ira FADEN
金额：
$ 33.8万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9332481
关键词：
Acute Address Affect Apoptosis Apoptotic Attenuated BCL2 gene Bcl-2 Homology Domain Binding Cell Death Chronic Clinical Cognitive deficits Complex Data Down-Regulation Event Failure Family Family member Foundations Gene Expression Genes Genetic Transcription Genetically Engineered Mouse Goals Impairment In Vitro Individual Injury Intervention Mediating MicroRNAs Mitochondria Modeling Mus Nervous System Physiology Neurologic Neurologic Deficit Neurologic Dysfunctions Neurons Outcome Pathway interactions Play Protein Family Proteins Puma Repression Role Stream Tertiary Protein Structure Testing Therapeutic Traumatic Brain Injury Untranslated RNA Up-Regulation Work attenuation central nervous system injury cytochrome c disability functional disability improved in vivo knockout gene member mortality motor deficit mouse model neuron apoptosis neuron loss neuroprotection novel novel therapeutics pro-apoptotic protein public health relevance response therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) leads to neuronal cell loss and associated motor and cognitive deficits. The underlying neuronal cell death is mediated through multiple interconnected mechanisms, which include activation of multiple BH3-only and multi BH-domain pro-apoptotic proteins. Our preliminary data show that early up-regulation of these pro-apoptotic Bcl2 family proteins occur in the cortex after TBI and may play a significant role in neuronal cell death. Furthermore, we show that changes in specific microRNAs such as miR- 23a and -27a may be an important regulator of these pathophysiologic events. We propose to use genetically engineered mouse models and central administration of miR mimics to test our central hypothesis that combined modulation of multiple pro-apoptotic BH3-only as well as multi BH-domain molecules via miR- 23a/27a mimics results in superior attenuation of neuronal damage and improved reduction in neurological deficits after TBI, compared to more targeted interventions directed toward individual BH3-only pathways. Specific Aims will show that: Aim 1. To determine the individual and additive neuroprotection provided by inhibiting specific pro-apoptotic Bcl2 molecules after TBI. Study #1.1 Demonstrate the effects of constitutive deletion of Puma, Noxa or Bim on neuronal loss and functional deficits after brain trauma. Study #1.2 Compare the additive neuroprotective effects of Puma-/-/Noxa-/-/Bim-/- triple KO with those of Bax-/- Bak-/- double KO on neuronal loss and functional deficits after brain trauma Aim 2. To examine the mechanisms underpinning the rapid down-regulation of miR23a/27a and identify their key targets in neuronal apoptosis in vitro. Study #2 Identify the regulators of transcription and key targets for miR23a/27a in various models of neuronal apoptosis Aim 3. To demonstrate the relative neuroprotective effects of miR-23a and -27a as well as their additive benefits and therapeutic window; examine their modulation and targets after TBI in vivo. Study #3.1 Examine effects of acute central (icv) administration of miR-23a and/or miR-27a mimics on neuronal loss and functional deficits after brain trauma Study #3.2 Examine the therapeutic window of delayed central (icv) administration of miR mimics on neuronal loss and functional deficits after brain trauma after TBI with an extended therapeutic window.