Reducing Neuronal Loss After Traumatic Brain Injury

减少脑外伤后的神经元损失

基本信息

批准号：
8919730
负责人：
PRAMOD K DASH
金额：
$ 42.34万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
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：
2015-07-15 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8919730
关键词：
Acids Animals Brain CCAAT-Enhancer-Binding Proteins Calcium Cause of Death Cell Count Cell Death Cell Survival Cells Cerebrum Cessation of life Chemicals Clinical Research Cognitive Contusions Data Dose Double-Stranded RNA Drug Combinations Endoplasmic Reticulum Excision FDA approved Free Radicals Functional disorder Future Glucose Guanabenz Hippocampus (Brain)Homeostasis Homologous Protein Hypoxia Individual Injury Lead Learning Mediating Mediator of activation protein Membrane Membrane Proteins Memory Molecular Molecular Chaperones Neurocognitive Neurocognitive Deficit Neurons Outcome Oxidative Stress Pathway interactions Peptide Initiation Factors Perfusion Persons Pharmaceutical Preparations Phosphoric Monoester Hydrolases Phosphorylation Phosphotransferases Play Production Property Protein Biosynthesis Protein Kinase Proteins Publishing Reporting Research Role Signal Pathway Signal Transduction Signaling Molecule Stimulus Testing Therapeutic Time Traumatic Brain Injury Ubiquitination Workload base biological adaptation to stress cognitive function controlled cortical impact detector disability eIF-2 Kinase endoplasmic reticulum stress experience improved injured neurocognitive test neuron loss neuroprotection newborn neuron protein degradation protein folding protein misfolding public health relevance research clinical testing response secretory protein translational study young adult

项目摘要

DESCRIPTION (provided by applicant): Moderate-severe traumatic brain injury (TBI) often causes neuronal death and neurocognitive impairments, with both immature and mature neurons being vulnerable to the injury. The endoplasmic reticulum (ER) plays a major role in the folding of membrane and secreted proteins and in calcium storage and intracellular calcium homeostasis. Its function can disrupted in response to decreased in response to a number of stimuli including reduced glucose levels, hypoxia, and altered calcium levels, all of which have been observed after TBI. Disrupted ER function (often referred to as ER stress) can result in the accumulation of misfolded proteins. One of the signaling pathways activated in response to ER stress is double-stranded RNA-activated protein kinase-like endoplasmic reticulum kinase (Perk). Once activated, Perk phosphorylates the translation initiation factor eIF2a, which acts to reduce global protein synthesis while permitting the synthesis of chaperones involved in protein folding. If ER function cannot be restored, Perk leads to the increased expression of CCAAT/enhancer-binding protein homologous protein (CHOP), a mediator of cell death. We have observed that TBI increases eIF2a phosphorylation and enhances CHOP expression. In order to examine the translational potential of targeting Perk-eIF2a-CHOP pathway, we have obtained preliminary experimental results to indicate that post injury administration of guanabenz (a FDA-approved drug that acts to inhibit eIF2a phosphatase) reduces neuronal loss and improves neurocognitive outcome. Furthermore, post-injury administration a chemical chaperone (4-phenylbuteric acid (4-PBA), an FDA-approved drug) also improved outcome. Based on these and other observations, we propose to test the hypothesis that post-TBI administration of guanabenz, 4-PBA, and their combination will effectively reduce loss of both mature and immature neurons and improve neurocognitive function. Aim 1: To determine efficacy of guanabenz and its therapeutic time window. Aim 2: To define the optimal dose and therapeutic time window for 4-PBA. Aim 3: To evaluate if the combination of guanabenz and 4-PBA is more efficacious. The results from these studies provide the basis for future clinical studies to determine if individual drugs alone or in combination can be used to improve outcome after TBI.

描述（由适用提供）：中期创伤性脑损伤（TBI）通常会导致神经元死亡和神经认知障碍，而未成熟和成熟的神经元都容易受到损伤。内质网（ER）在膜和分泌蛋白的折叠以及钙储存和细胞内钙稳态中起着重要作用。由于响应许多刺激，包括葡萄糖水平降低，缺氧和钙水平变化，因此可以禁用其功能，以响应降低。破坏的ER功能（通常称为ER应力）可能导致错误折叠蛋白的积累。响应于ER应激而激活的信号通路之一是双链RNA激活的蛋白激酶样性内质网激酶（PERK）。一旦激活，PERK磷酸化了翻译起始因子EIF2A，该系数可减少全局蛋白质合成，同时允许合成涉及蛋白质折叠的链酮。如果无法恢复ER功能，PERK会导致CCAAT/增强子结合蛋白同源蛋白（CHOP）的表达增加，这是细胞死亡的介体。我们已经观察到TBI增加了EIF2A磷酸化并增强了CHOP表达。为了检查靶向PERK-EIF2A-CHOP途径的翻译潜力，我们获得了初步的实验结果，以表明胰鸟本兹的损伤后给药（一种由FDA批准的药物抑制EIF2A磷酸酶），减少了神经遗传丧失并改善神经知名的结果。此外，伤害后给药化学链酮（4-苯基二酸（4-PBA），一种由FDA批准的药物）也改善了预后。基于这些和其他观察结果，我们建议检验以下假设：TBI后甘原，4-PBA及其组合将有效地减少成熟和未成熟神经元的丧失并改善神经认知功能。目的1：确定鸟传及其治疗时间窗口的有效性。目标2：定义4-PBA的最佳剂量和治疗时间窗口。 AIM 3：评估鸟根和4-PBA的组合是否更有效。这些研究的结果为将来的临床研究提供了基础，以确定单独或组合是否可以使用单独的药物来改善TBI后的结果。