miR-711 regulation of neuronal cell death after traumatic brain injury

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，其中包括抑制几种神经保护途径。我们的初步数据表明，早期下调的生存途径，包括Akt发生在皮层TBI后，并可能发挥重要作用，在转向神经元细胞死亡的生存/凋亡平衡。此外，我们发现，快速升高的选择microRNA，如miR-711可能是这些病理生理事件的重要调节因子。我们建议在体外和体内神经元损伤模型中使用各种分子技术，包括miR抑制剂的中枢和全身给药，以测试我们的中心假设，即响应于miR-711上调的多种神经保护机制的抑制导致促凋亡途径的不受约束的激活，并代表TBI后神经元损失和神经功能缺损的关键机制。具体目标：目标1。确定miR-711在神经元细胞死亡中的调控和机制作用。研究#1.1证明miR-711的快速升高是多种神经元凋亡模型中的关键细胞死亡途径。研究#1.2表征神经元凋亡中miR-711启动子活性。研究#1.3表征miR-711在神经元凋亡中的靶标。目标2.研究实验性TBI后miR-711的调控和miR-711依赖性神经细胞死亡的机制。研究#2.1证明miR-711的快速升高导致TBI后神经元细胞死亡。研究#2.2确定miR-711的关键分子靶点及其对TBI后凋亡途径的影响。研究#2.3 TBI后鉴定miR-711转录调节剂。目标3.检查miR-711抑制剂在中枢和/或全身给药后的神经保护作用，并确定CCI后的治疗窗。研究#3.1确定miR-711抑制剂中枢（icv）给药对脑创伤后神经元损失和功能缺陷的治疗窗。研究#3.2检查全身施用miR抑制剂对脑创伤后神经元损失和功能缺陷的治疗作用。

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 inhibition of several neuroprotective pathways. Our preliminary data show that early down-regulation of survival pathways including Akt occur in the cortex after TBI and may play a significant role in shifting the survival/apoptosi balance toward neuronal cell death. Furthermore, we show that rapid elevation in select microRNAs such as miR-711 may be an important regulator of these pathophysiologic events. We propose to use various molecular techniques in in vitro and in vivo neuronal injury models including central and systemic administration of miR inhibitors to test our central hypothesis that inhibition of multiple neuroprotective mechanisms in response to miR-711 up-regulation leads to unconstrained activation of pro-apoptotic pathways and represents a key mechanism of neuronal loss and neurological deficits after TBI. Specific Aims: Aim 1. To determine the miR-711 regulation and mechanistic effects in neuronal cell death. STUDY #1.1 Demonstrate that rapid elevation of miR-711 is a key cell death pathway in multiple models of neuronal apoptosis. STUDY #1.2 Characterize the miR-711 promoter activity in neuronal apoptosis. STUDY #1.3 Characterize the targets of miR-711 in neuronal apoptosis. Aim 2. To examine the miR-711 regulation and mechanisms of miR-711-dependent neuronal cell death after experimental TBI. Study #2.1 Demonstrate that rapid elevation of miR-711 leads to neuronal cell death after TBI. Study #2.2 Identify key molecular targets of miR-711 and its impact on apoptotic pathways after TBI. Study #2.3 Identify miR-711 transcriptional modulators after TBI. Aim 3. To examine the neuroprotective effects of miR-711 inhibitors following central and/or systemic administration as well as to determine their therapeutic window after CCI. Study #3.1 Determine the therapeutic window of central (icv) administration of miR-711 inhibitors on neuronal loss and functional deficits after brain trauma. Study #3.2 Examine the therapeutic effects of systemic administration of miR inhibitors on neuronal loss and functional deficits after brain trauma.