Elucidating the role of the eIF2alpha kinase PERK in synaptic plasticity and memo

阐明 eIF2α 激酶 PERK 在突触可塑性和备忘录中的作用

• 批准号: 7924625
• 负责人: My Ai Trinh
• 金额: $ 2.52万
• 依托单位: NEW YORK UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7924625
• 关键词: Address; Affect; Agonist; Alleles; Alzheimer' s Disease; Area; Behavior; Binding; Biochemical; Brain Ischemia; CCAAT-Enhancer-Binding Proteins; Cellular Stress; Cellular Stress Response; Cognition Disorders; Complex; Coupled; D Aspartate; Endoplasmic Reticulum; Eukaryota; Fragile X Syndrome; Gene Expression; Generations; Genetic Translation; Goals; Guanine Nucleotide Exchange Factors; Hippocampus (Brain); Human; Knock-out; Laboratories; Lead; Learning; Long-Term Depression; Long-Term Potentiation; Mediating; Memory; Messenger RNA; Metabotropic Glutamate Receptors; Modeling; Molecular; Mus; Natural regeneration; Nerve Growth Factor Receptors; Neurodegenerative Disorders; Neurologic; Neurotransmitters; Open Reading Frames; Pancreas; Parkinson Disease; Phorbol Esters; Phosphorylation; Phosphotransferases; Play; Process; Prosencephalon; Protein Biosynthesis; Protein Kinase; Proteins; Recycling; Regulation; Ribosomes; Role; Series; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Slice; Synapses; Synaptic plasticity; Testing; Translation Initiation; Translations; Tuberous Sclerosis; Universities; X-Linked Mental Retardation; activating transcription factor 4; aspartate receptor; eIF-2 Kinase; interest; long term memory; meetings; nervous system disorder; promoter; recombinase; research study

DESCRIPTION (provided by applicant): The overall goal of our lab is to understand the complex molecular mechanisms underlying synaptic plasticity and vertebrate memory formation. My goal is to determine the specific role that the RNA-dependent protein kinase-like endoplasmic reticulum (ER) elF2a kinase (PERK) plays in regulating translation during these processes. PERK primarily has been studied in pancreatic cellular stress response and global brain ischemia; however, its role in protein synthesis-dependent hippocampal synaptic plasticity is poorly understood. In the hippocampus, the generation of new proteins has been shown to be regulated during plasticity via factors involved in the initiation of mRNA translation. A key regulatory step in the initiation of translation is the formation of the preinitiation ternary complex elF2-GTP-Met-tRNAiMet, which is required to bind to the 40S ribosome prior to recognition of mRNA. Upon each round of translation initiation, the guanine-nucleotide exchange factor, elF2B, is required to recycle elF2-GDP to elF2-GTP to regenerate the ternary complex. It has been shown that phosphorylation of the a subunit of elF2 inhibits elF2B activity and eventually decreases translation. Under specific cellular stress conditions, such as an accumulation of unfolded proteins in the ER, PERK phosphorylates elF2a and functions to downregulate general protein synthesis. Understanding the molecular mechanism underlying synaptic plasticity and memory formation is critical to understanding how errors in these processes can lead to cognitive disorders. To this end, I propose experimental research aimed at examining the role of PERK in hippocampus-dependent behavior, synaptic plasticity and the regulation of signal transduction pathways critical to hippocampal long-term potentiation (LTP), long-term depression (LTD) and memory. Specifically, I aim to address the following hypothesis: 1) mGluR-induced PKC signaling modulates PERK-directed elF2a phosphorylation and PERK- dependent translation; 2) PERK is required for the expression of normal hippocampal mGluR-LTD; and 3) PERK is required for hippocampus-dependent forms of learning and memory. Altered protein synthesis has been shown to accompany several human neurological disorders and neurodegenerative diseases including Fragile X linked mental retardation, Alzheimer's disease (AD), Parkinson's disease (PD) and tuberous sclerosis. Thus, abnormal PERK function could be a significant factor underlying the manifestation in severe, debilitating neurological conditions, whereas normal PERK function could play a key role in the molecular mechanisms involved in learning and memory.

描述（申请人提供）：我们实验室的总体目标是了解突触可塑性和脊椎动物记忆形成的复杂分子机制。我的目标是确定RNA依赖性蛋白激酶样内质网（ER）eIF 2a激酶（PERK）在这些过程中调节翻译的具体作用。PERK主要在胰腺细胞应激反应和全脑缺血中进行了研究;然而，其在蛋白质合成依赖性海马突触可塑性中的作用知之甚少。在海马体中，新蛋白质的产生已被证明是通过参与mRNA翻译起始的因子在可塑性过程中进行调节的。翻译起始中的关键调节步骤是形成起始前三元复合物eIF 2-GTP-Met-tRNAiMet，其需要在mRNA识别之前结合40 S核糖体。在每轮翻译起始时，需要鸟嘌呤-核苷酸交换因子eIF 2B将eIF 2-GDP再循环为eIF 2-GTP以再生三元复合物。已经显示eIF 2的α亚基的磷酸化抑制eIF 2B活性并最终降低翻译。在特定的细胞应激条件下，例如ER中未折叠蛋白的积累，PERK磷酸化eIF 2a并起到下调一般蛋白质合成的作用。了解突触可塑性和记忆形成的分子机制对于理解这些过程中的错误如何导致认知障碍至关重要。为此，我提出了实验研究，旨在研究PERK在海马依赖性行为，突触可塑性和海马长时程增强（LTP），长时程抑制（LTD）和记忆的信号转导通路的调节中的作用。具体地，我的目标是解决以下假设：1）mGluR诱导的PKC信号传导调节PERK指导的eIF 2a磷酸化和PERK依赖性翻译; 2）PERK是正常海马mGluR-LTD表达所需的;和3）PERK是海马依赖性形式的学习和记忆所需的。蛋白质合成的改变已被证明伴随着几种人类神经系统疾病和神经退行性疾病，包括脆性X染色体连锁的精神发育迟滞、阿尔茨海默病（AD）、帕金森病（PD）和结节性硬化症。因此，异常的PERK功能可能是严重的、使人衰弱的神经系统疾病的表现的重要因素，而正常的PERK功能可能在参与学习和记忆的分子机制中发挥关键作用。