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

描述(申请人提供)：创伤性脑损伤(TBI)导致神经细胞丢失和相关的运动和认知障碍。潜在的神经细胞死亡是通过多种相互联系的机制来调节的，其中包括抑制几个神经保护通路。我们的初步数据显示，包括Akt在内的生存通路在脑创伤后早期在大脑皮层发生下调，并可能在将存活/细胞凋亡平衡转向神经细胞死亡方面发挥重要作用。此外，我们还表明，miR-711等特定microRNAs的快速升高可能是这些病理生理事件的重要调节因素。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，包括中枢和全身应用miR抑制剂来验证我们的中心假设，即抑制miR-711上调反应的多种神经保护机制会导致促凋亡通路的不受约束的激活，并代表着脑创伤后神经元丢失和神经功能障碍的关键机制。目的：1.探讨miR-711在神经细胞死亡中的调控和机制作用。研究1.1表明，miR-711的快速上调是多种神经细胞凋亡模型中的关键细胞死亡途径。研究1.2表征miR-711启动子在神经细胞凋亡中的活性。研究1.3确定miR-711在神经细胞凋亡中的靶点。目的2.探讨实验性脑创伤后miR-711对依赖miR-711的神经细胞死亡的调节作用及其机制。研究#2.1表明，脑外伤后miR-711的快速升高导致神经细胞死亡。研究#2.2确定miR-711的关键分子靶点及其对脑损伤后细胞凋亡途径的影响。研究#2.3确定脑损伤后miR-711转录调节因子。目的3.研究miR-711抑制剂在中枢和/或全身给药后的神经保护作用，并确定其在CCI后的治疗窗口。研究3.1确定脑创伤后中枢(Icv)给药miR-711抑制剂对神经元丢失和功能障碍的治疗窗口。研究3.2考察全身应用miR抑制剂对脑创伤后神经元丢失和功能障碍的治疗效果。

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.