Protein Kinase B and C in Head Injury

头部损伤中的蛋白激酶 B 和 C

基本信息

批准号：
7175341
负责人：
LARRY W JENKINS
金额：
$ 32.56万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-02-15 至 2009-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7175341
关键词：
3-Phosphoinositide Dependent Protein Kinase-1 70-kDa Ribosomal Protein S6 Kinases Actins Acute Adult Adverse effects Antibodies Back Binding Body Weight decreased Brain Brain region Catabolism Cell physiology Cerebral Ischemia Childhood Chronic Clinical Clinical Treatment Clinical Trials Craniocerebral Trauma Cycloheximide Depressed mood Development Enzymes Eukaryotic Initiation Factor-2 FGF2 gene Family Fibroblast Growth Factor 2 Functional disorder GRP78 gene Glutamate Dehydrogenase Glutamate-Ammonia Ligase Glutamates Glycogen (Starch) Synthase Glycogen Synthase Kinase 3 Growth Heart Arrest Heat shock proteins Hippocampus (Brain)Hour IGF2 gene Immunochemistry Immunohistochemistry Injury Insulin-Like Growth Factor II Internal Ribosome Entry Site Ipsilateral Ischemia Ischemic Brain Injury Lasers Learning Link MALDI-TOF Mass Spectrometry Mediating Memory Mitogen-Activated Protein Kinases Modeling Numbers Pathway interactions Peptide Initiation Factors Phase Phosphatidylinositols Phosphorylation Phosphotransferases Process Production Protein Biosynthesis Protein Kinase Protein Kinase C Protein Synthesis Inhibition Proteins Proto-Oncogene Proteins c-akt Rain Rate Rattus Recovery Recovery of Function Secondary to Shock Sirolimus Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization Stress Synaptic plasticity Temperature Therapeutic Therapeutic Effect Time Translations Traumatic Brain Injury Tubulin Vimentin Weight Weight Gain Western Blotting base chromosome 5q loss citrate carrier cognitive function controlled cortical impact day eIF4 Regulation Pathway enolase functional outcomes gel electrophoresis human FRAP1 protein human TYRP1 protein immature animal improved interest ionization link protein mTOR protein natural hypothermia neuronal survival postnatal protein expression protein kinase C zeta protein phosphatase inhibitor-2 response spatial relationship stress protein two-dimensional

项目摘要

DESCRIPTION (provided by applicant): The protein kinase B (PKB) and protein kinase C (PKC) enzyme families participate in many cellular functions including protein synthesis. Catabolism, weight loss, and impaired developmental body and brain weight gains have been documented after pediatric traumatic brain injury (TBI). Hypothermia treatment has been shown to improve developmental brain weight in specific brain regions important in cognitive function such as the hippocampus and spatial memory after injury. However, recent study has shown that pediatric TBI alters hippocampal protein synthesis and while hypothermia improves protein synthesis recovery after cerebral ischemia, this has not been examined after TBI in either adult or immature animals. Hypothermia is a unique modulator of protein synthesis in that it depresses overall protein synthesis but selectively increases cap-independent synthesis of stress proteins via cold shock stress. Hippocampal protein synthesis after TBI is critical for neuronal survival, learning and memory, and synaptic plasticity. Pathological changes in protein synthesis mediated by dysfunction of eukaryotic initiation factor 2 (eIF2) and 4 (eIF4) pathways after pediatric TBI may impair the initiation and fidelity of protein synthesis and injury related restorative and growth responses. We have recently shown that hippocampal eIF2 and eIF4 pathway regulation is altered acutely (2- 72hrs) and possibility up to 2 wk after TBI to the 17 day postnatal (PND) rat. We have also shown moderate hypothermia reduces a key injury eIF2 pathway abnormality. Pathological changes in the phosphoinositide 3-kinase - protein kinase B (PI3K-PKB), protein kinase C (PKC), glycogen synthase 3 (GSK-3), mitogen activated protein kinase (MAPK) and target of rapamycin kinase (mTOR) pathways are all involved in our model. Protein synthesis can be modified by cap-dependent (eIF4E), cap-independent (IRES -internal ribosome entry segment), and 5TOP - 5' oligopyrimidine tract (mTOR) protein synthesis initiation. We hypothesize that post-injury hypothcrmia promotes functional recovery following pediatric TBI not primarily due to inhibition of excitotoxic glutamate release (which has already occurred), but by activating beneficial stress related IRES protein synthesis causing cold stress induced tolerance to secondary injury processes. We propose: 1) Impaired IRES protein translation occurs primarily after moderate pediatric TBI. Changes in hippocampal PI3K-PKB and mTOR kinase pathways that impair cap-binding (elF4E) and 5'TOP initiation phases of protein synthesis also occur but are of less magnitude. 2) The overall rate of protein synthesis (controlled by elF2) is reduced due to acute and chronic PKC zeta and GSK-3 inhibition of eIF2beta, and 3)That therapeutic modulation with mild hypothermia after pediatric TBI will enhance functional recovery by increasing IRES protein synthesis via cold shock stimulated production of beneficial IRES linked protein expression and elF2B recovery.

描述（由申请人提供）：蛋白激酶B（PKB）和蛋白激酶C（PKC）酶家族都参与包括蛋白质合成在内的许多细胞功能。小儿创伤性脑损伤（TBI）后，已经记录了分解代谢，体重减轻和发育体重受损。体温过低的治疗已被证明可以改善在认知功能中重要的特定大脑区域的发育性脑体重，例如海马和损伤后的空间记忆。然而，最近的研究表明，小儿TBI改变了海马蛋白的合成，而低温可改善脑缺血后蛋白质的合成恢复，但在成年或不成熟动物中TBI后尚未对此进行检查。体温过低是蛋白质合成的独特调节剂，因为它会降低整体蛋白质的合成，但通过冷休克应激选择性地增加了与应力蛋白质无关的合成。 TBI后的海马蛋白合成对于神经元的生存，学习和记忆以及突触可塑性至关重要。小儿TBI后，由真核起始因子2（EIF2）和4（EIF4）途径功能障碍介导的蛋白质合成的病理变化可能会损害蛋白质合成以及相关的蛋白质相关恢复和生长反应的起始和忠诚度。我们最近表明，海马EIF2和EIF4途径调节被急性改变（2-72小时），在TBI后至17天后到产后（PND）大鼠，可能性高达2周。我们还显示中度的低温降低了关键损伤EIF2途径异常。磷酸肌醇3-激酶的病理变化 - 蛋白激酶B（PI3K-PKB），蛋白激酶C（PKC），糖原合成酶3（GSK-3），有丝分裂原活化蛋白激酶（MAPK）和RAPAMYCIN激酶（MTOR）途径的靶标都参与了我们的模型。蛋白质合成可以通过cap依赖性（EIF4E），帽独立（IRES-内部核糖体进入段）和5TOP -5'寡吡啶氨酸（MTOR）蛋白质合成起始来修饰。我们假设伤害后的下降刺激促进小儿TBI后的功能恢复并不主要是由于抑制兴奋性谷氨酸释放（已经发生了），而是通过激活有益的应激相关IRES蛋白合成，从而导致冷应激引起的冷应力诱导对次要损伤过程的耐受性。我们提出：1）IRES蛋白翻译受损主要发生在中等小儿TBI之后。蛋白质合成的海马PI3K-PKB和MTOR激酶途径的变化和MTOR激酶途径的变化也会发生蛋白质合成的5''TOP启动阶段，但也较小。 2）由于急性和慢性PKC Zeta和GSK-3对EIF2Beta的抑制以及3）3）在儿科TBI后用轻度低温调节而导致蛋白质合成的总体速率（由ELF2控制）降低通过冷休克的合成刺激了有益的IRES的产生，将蛋白质表达和ELF2B恢复联系起来。