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:
  • 金额:
    $ 33.8万
  • 依托单位:
  • 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

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.
 描述(由申请人提供):创伤性脑损伤(TBI)导致神经元细胞丢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,其包括多种仅BH 3和多BH结构域促凋亡蛋白的激活。我们的初步数据表明,早期上调这些促凋亡Bcl 2家族蛋白发生在脑外伤后的皮层,并可能在神经元细胞死亡中发挥重要作用。此外,我们发现特定microRNA如miR-23 a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模拟物的中央给药来测试我们的中心假设,即与针对单个仅BH 3途径的更有针对性的干预相比,通过miR-23 a/27 a模拟物组合调节多种促凋亡仅BH 3以及多BH结构域分子导致TBI后神经元损伤的上级衰减和神经功能缺损的改善减少。具体目标将显示:目标1。确定TBI后通过抑制特异性促凋亡Bcl 2分子提供的个体和累加神经保护作用。研究#1.1证明Puma、Noxa或Bim组成性缺失对脑创伤后神经元损失和功能缺陷的影响。研究#1.2比较Puma-/-/Noxa-/-/Bim-/-三重KO与Bax-/-巴克-/-双KO对脑创伤后神经元损失和功能缺陷的累加神经保护作用目的2.研究miR 23 a/27 a快速下调的机制,并确定其在体外神经元凋亡中的关键靶点。研究#2鉴定各种神经元凋亡模型中miR 23 a/27 a的转录调节因子和关键靶点为了证明miR-23 a和-27 a的相对神经保护作用以及它们的附加益处和治疗窗;在体内TBI后检查它们的调节和靶点。研究#3.1检查miR-23 a和/或miR-27 a模拟物的急性中枢(icv)施用对脑创伤后神经元损失和功能缺陷的影响研究#3.2检查miR模拟物的延迟中枢(icv)施用对TBI后脑创伤后神经元损失和功能缺陷的治疗窗,具有延长的治疗窗。

项目成果

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ALAN Ira FADEN其他文献

ALAN Ira FADEN的其他文献

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{{ truncateString('ALAN Ira FADEN', 18)}}的其他基金

Bidirectional Brain-Gut interactions, chronic neuroinflammation and neurodegeneration after traumatic brain injury
双向脑肠相互作用、脑外伤后慢性神经炎症和神经退行性变
  • 批准号:
    10684129
  • 财政年份:
    2022
  • 资助金额:
    $ 33.8万
  • 项目类别:
Bidirectional Brain-Gut interactions, chronic neuroinflammation and neurodegeneration after traumatic brain injury
双向脑肠相互作用、脑外伤后慢性神经炎症和神经退行性变
  • 批准号:
    10517782
  • 财政年份:
    2022
  • 资助金额:
    $ 33.8万
  • 项目类别:
Mechanism of Inflammatory Related Brain Dysfunction after Spinal Cord Injury
脊髓损伤后炎症相关脑功能障碍的机制
  • 批准号:
    10597985
  • 财政年份:
    2019
  • 资助金额:
    $ 33.8万
  • 项目类别:
Reprogramming Microglial Epigenetic Pathways to Promote Cognitive Recovery after Brain Trauma.
重新编程小胶质细胞表观遗传途径以促进脑外伤后的认知恢复。
  • 批准号:
    10381618
  • 财政年份:
    2019
  • 资助金额:
    $ 33.8万
  • 项目类别:
Reprogramming Microglial Epigenetic Pathways to Promote Cognitive Recovery after Brain Trauma.
重新编程小胶质细胞表观遗传途径以促进脑外伤后的认知恢复。
  • 批准号:
    9884830
  • 财政年份:
    2019
  • 资助金额:
    $ 33.8万
  • 项目类别:
Mechanism of Inflammatory Related Brain Dysfunction after Spinal Cord Injury
脊髓损伤后炎症相关脑功能障碍的机制
  • 批准号:
    10380183
  • 财政年份:
    2019
  • 资助金额:
    $ 33.8万
  • 项目类别:
Reprogramming Microglial Epigenetic Pathways to Promote Cognitive Recovery after Brain Trauma.
重新编程小胶质细胞表观遗传途径以促进脑外伤后的认知恢复。
  • 批准号:
    10596517
  • 财政年份:
    2019
  • 资助金额:
    $ 33.8万
  • 项目类别:
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
  • 财政年份:
    2015
  • 资助金额:
    $ 33.8万
  • 项目类别:
Mechanisms and Modulation of Cell Death in Traumatic Brain Injury
创伤性脑损伤中细胞死亡的机制和调节
  • 批准号:
    8090307
  • 财政年份:
    2009
  • 资助金额:
    $ 33.8万
  • 项目类别:
Combination drug treatment to inhibit multiple cell death pathways after TBI
抑制 TBI 后多种细胞死亡途径的联合药物治疗
  • 批准号:
    7985713
  • 财政年份:
    2009
  • 资助金额:
    $ 33.8万
  • 项目类别:

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