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

• 批准号: 9760010
• 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
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9760010
• 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; neuron apoptosis; neuron loss; neuroprotection; novel; novel therapeutics; pro-apoptotic protein; public health relevance; response; therapeutic target

 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.

 描述（由申请人提供）：创伤性脑损伤（TBI）导致神经元细胞损失以及相关的运动和认知缺陷，潜在的神经元细胞死亡是通过多种相互关联的机制介导的，其中包括多个仅 BH3 结构域和多个 BH 结构域的激活。我们的初步数据表明，TBI 后大脑皮层中这些促凋亡 Bcl2 家族蛋白的早期上调可能在神经细胞死亡中发挥重要作用。此外，我们表明，特定 microRNA（例如 miR-23a 和 -27a）的变化可能是这些病理生理事件的重要调节因子。我们建议使用基因工程小鼠模型和 miR 模拟物的中央管理来测试我们的中心假设，即结合调节 miR-23a 和 -27a。通过 miR-23a/27a 模拟物的多个促凋亡 BH3 结构域分子以及多个 BH 结构域分子可显着减轻神经元损伤，并改善神经功能损伤的减少与针对个体 BH3 通路的更有针对性的干预相比，TBI 后的缺陷研究将表明： 目标 1. 确定 TBI 后通过抑制特定促凋亡 Bcl2 分子提供的个体和附加神经保护。 Puma、Noxa 或 Bim 的组成性缺失对脑外伤后神经元损失和功能缺陷的影响研究#1.2 比较附加的神经保护作用。 Puma-/-/Noxa-/-/Bim-/- 三重 KO 与 Bax-/- Bak-/- 双重 KO 对脑外伤后神经损失和功能缺陷的影响 目标 2. 研究快速下调的机制miR23a/27a 的调节并确定其在体外神经细胞凋亡中的关键靶标研究 #2 确定各种神经元凋亡模型中 miR23a/27a 的转录调节因子和关键靶标。 3. 证明 miR-23a 和 -27a 的相对神经保护作用及其附加益处和治疗窗口；研究 TBI 后体内的调节和靶标研究 #3.1 检查 miR-23a 和 -27a 的急性中枢 (icv) 给药的效果。 23a 和/或 miR-27a 模拟物对脑外伤后神经元损失和功能缺陷的影响研究 #3.2 检查 miR 模拟物延迟中枢 (icv) 给药对神经元损失和功能缺陷的治疗窗TBI 后脑外伤后的功能缺陷，具有延长的治疗窗口。

项目成果

Comparing effects of CDK inhibition and E2F1/2 ablation on neuronal cell death pathways in vitro and after traumatic brain injury.

• DOI: 10.1038/s41419-018-1156-y
• 发表时间: 2018-11-06
• 期刊: Cell death & disease
• 影响因子: 9
• 作者: Aubrecht TG;Faden AI;Sabirzhanov B;Glaser EP;Roelofs BA;Polster BM;Makarevich O;Stoica BA
• 通讯作者: Stoica BA