PROTEIN SYNTHESIS MEMORY AND PEDIATRIC BRAIN INJURY

蛋白质合成记忆与小儿脑损伤

• 批准号: 6394392
• 负责人: LARRY W JENKINS
• 金额: $ 18.75万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-05-15 至 2003-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6394392
• 关键词: autoradiography; brain injury; enzyme activity; enzyme induction /repression; genetic translation; heat shock proteins; immature animal; insulinlike growth factor; laboratory rat; learning disorders; memory; neural cell adhesion molecules; neuropharmacology; nonhuman therapy evaluation; pediatrics; protein biosynthesis; protein kinase C; protein tyrosine kinase; space perception; translation factor; trauma; western blottings

This is an exploratory R21application in response to PA number PAS-99-080. Traumatic brain injury (TBI) is the leading cause of death and disability in traumatically injured children. Additionally, children suffer diffuse TBI more often than adults and we have developed a reproducible and clinically relevant model of diffuse pediatric TBI in the rat. This model produces cognitive deficits in spatial memory, as assessed by the Morris Water Maze (MWM) task, which is uncomplicated by acute or delayed forebrain neuronal death either related to injury or developmental apoptosis. Cognitive dysfunction is the most persistent consequence of pediatric TBI and the hippocampus plays crucial roles in experimental and clinical TBI cognitive impairment. Recent studies have implicated hippocampal protein synthesis after brain injury in neuronal survival or active death programs; however, protein synthesis is also critical for hippocampal dependent learning and memory. The neural cell adhesion molecule (NCAM) has been associated with hippocampal synaptic plasticity both during development in the immature and learning in the adult rat. The consolidation phase of spatial memory acquisition is prevented by inhibiting the synthesis of new proteins such as NCAM during learning of the MWM task. Impaired translation of new proteins may contribute to enduring learning deficits after pediatric TBI. Specifically, pathological changes in two key protein synthesis initiation pathways mediated by dysfunction of eIF2 and eIF4 initiation factor proteins may contribute to cognitive deficits after pediatric TBI. Critical roles for protein kinase C (PKC) and protein tyrosine kinase (PTK) activity in the initiation and fidelity of protein synthesis and in modulating injury related stress responses have been documented. Changes in PKC and PTK levels persist for days after adult TBI but have not been evaluated in pediatric TBI. Protein kinase activity can be modulated by exogenously administered insulin growth factor-I (IGF-1) which has also been shown to improve outcome in adult clinical and experimental TBI. We propose: 1) that pediatric TBI also produces persistent changes in PKC and PTK function impairing the initiation phase of protein synthesis and reducing the translation of key proteins such as NCAM necessary for spatial memory learning in the MWM paradigm. 2) that therapeutic modulation of PKC and PTK activity (at 2 wk after injury) with insulin growth factor-I will improve spatial memory after TBI and will help normalize protein synthesis and the expression of NCAM during MWM learning.

这是响应 PA 编号 PAS-99-080 的探索性 R21 应用。 创伤性脑损伤（TBI）是创伤儿童死亡和残疾的主要原因。此外，儿童比成人更容易遭受弥漫性 TBI，我们已经在大鼠中开发了一种可重复且具有临床相关性的弥漫性儿科 TBI 模型。 根据莫里斯水迷宫（MWM）任务的评估，该模型产生空间记忆认知缺陷，与损伤或发育性细胞凋亡相关的急性或延迟性前脑神经元死亡并不复杂。 认知功能障碍是儿童 TBI 最持久的后果，海马在实验和临床 TBI 认知障碍中起着至关重要的作用。 最近的研究表明，脑损伤后海马蛋白的合成与神经元的存活或主动死亡程序有关。然而，蛋白质合成对于海马依赖性学习和记忆也至关重要。 神经细胞粘附分子（NCAM）与未成熟大鼠的发育和成年大鼠的学习过程中的海马突触可塑性有关。 通过在学习 MWM 任务期间抑制 NCAM 等新蛋白质的合成，可以防止空间记忆获取的巩固阶段。新蛋白质的翻译受损可能会导致儿童创伤性脑损伤后持续的学习缺陷。 具体来说，由 eIF2 和 eIF4 起始因子蛋白功能障碍介导的两个关键蛋白质合成起始途径的病理变化可能会导致儿童 TBI 后的认知缺陷。 蛋白激酶 C (PKC) 和蛋白酪氨酸激酶 (PTK) 活性在蛋白质合成的起始和保真度以及调节损伤相关应激反应中的关键作用已被记录。 成人 TBI 后 PKC 和 PTK 水平的变化持续数天，但尚未在儿童 TBI 中进行评估。 蛋白激酶活性可以通过外源性胰岛素生长因子-I (IGF-1) 进行调节，这也已被证明可以改善成人临床和实验性 TBI 的结果。 我们建议：1）儿科 TBI 还会产生 PKC 和 PTK 功能的持续变化，损害蛋白质合成的起始阶段，并减少 MWM 范式中空间记忆学习所需的关键蛋白质（例如 NCAM）的翻译。 2) 用胰岛素生长因子-I 对 PKC 和 PTK 活性（损伤后 2 周）进行治疗性调节将改善 TBI 后的空间记忆，并有助于在 MWM 学习期间使蛋白质合成和 NCAM 表达正常化。