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

miR-711对脑外伤后神经细胞死亡的调节

基本信息

批准号：
9906940
负责人：
BOGDAN ADRIAN STOICA
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：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9906940
关键词：
AKT inhibition ANGPT1 gene Address Affective Apoptotic Attenuated Brain Injuries Caspase Cell Death Chronic Clinical Cognitive Cognitive deficits Complex Data Down-Regulation Equilibrium Event Experimental Models Failure Family member Foundations Gene Expression Genes Genetic Transcription Goals Heat-Shock Proteins 70 Impairment In Vitro Individual Injury Mediating MicroRNAs Mitochondria Modeling Molecular Molecular Target Motor Mus Nerve Degeneration Nervous System Physiology Neurologic Neurologic Deficit Neurologic Dysfunctions Neuronal Injury Outcome Pathology Pathway interactions Play Process Regulation Role Signal Transduction Techniques Testing Therapeutic Therapeutic Effect Therapeutic Intervention Tissues Transcriptional Activation Traumatic Brain Injury Treatment Efficacy Untranslated RNA Up-Regulation Work apoptosis inducing factor attenuation clinically relevant cytochrome c design disability effective therapy improved in vivo inhibitor/antagonist mortality motor deficit neuron apoptosis neuron loss neuroprotection novel novel therapeutics promoter public health relevance repaired 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 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.

描述（由申请人提供）：创伤性脑损伤（TBI）导致神经元细胞丧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互连机制介导的，其中包括抑制几种神经保护途径。我们的初步数据表明，在TBI之后，包括AKT在内的生存途径的早期下调发生在皮层中，并且可能在将生存/apoptosi平衡转向神经元细胞死亡方面起重要作用。此外，我们表明，诸如miR-711之类的精选microRNA中的快速升高可能是这些病理生理事件的重要调节剂。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，包括中心和全身施用miR抑制剂，以测试我们的中心假设，即抑制多种神经保护机制，响应miR-711上调的上调导致促进型途径和neurronodic of Neuronolonolonodic of Neuronolonolonolonicy of Neuronolonolonolon of neuronolonolonodic of Neuronolonolonic of Neuronolonolonic of Neuronolonolonodic and neuronolonolon of neuronolonolonoloin of neuronolonolon of neuronolonolon saven sapert。具体目的：目的1。确定神经元细胞死亡中的miR-711调节和机械作用。研究＃1.1表明，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是神经元凋亡中miR-711启动子活性的特征。研究＃1.3表征了神经元凋亡中miR-711的靶标。目标2。检查实验性TBI后miR-711依赖性神经元细胞死亡的miR-711调节和机制。研究＃2.1表明，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的关键分子靶标及其对TBI后凋亡途径的影响。研究＃2.3 TBI后识别miR-711转录调节剂。目的3。检查中央和/或全身给药后miR-711抑制剂的神经保护作用，并确定CCI后其治疗窗口。研究＃3.1确定miR-711抑制剂中央（ICV）对神经元丧失和脑创伤后功能缺陷的治疗窗口。研究＃3.2检查了全身施用MIR抑制剂对脑外伤后神经元丧失和功能缺陷的治疗作用。