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Translational Control in Memory and Brain Disorders

记忆和大脑疾病的翻译控制

基本信息

批准号：
10613505
负责人：
Eric Klann
金额：
$ 109.6万
依托单位：
NEW YORK UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-01 至 2029-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10613505
关键词：
Address Affinity Alzheimer&apos s Disease Alzheimer&apos s disease model Amygdaloid structure Auditory Behavior Behavioral Paradigm Biochemical Brain Diseases Cells Complex Discrimination Disease EIF-2alpha Electrophysiology (science)Event Extinction Fragile X Syndrome Functional disorder Genetically Engineered Mouse Hippocampus Laboratories Learning Measures Memory Memory Disorders Messenger RNA Methods Molecular Mus Neurodegenerative Disorders Neurodevelopmental Disorder Pathway interactions Peptide Initiation Factors Prefrontal Cortex Protein Biosynthesis Proteins Proteomics Ribosomes Rodent Role Signal Pathway Synapses Synaptic plasticity Translating Translational Regulation Translations Virus autism spectrum disorder cell type excitatory neuron immunocytochemistry in vivo inhibitory neuron innovation insight long term memory mRNA Translation memory consolidation memory process mouse model multidisciplinary new therapeutic target novel receptor ribosome profiling therapeutic target

项目摘要

Project Summary/Abstract Over the last 15 years, several laboratories, including my laboratory, have identified multiple signaling pathways that regulate translation via the translation initiation factors eIF4E and eIF2α during protein synthesis-dependent forms of long-lasting synaptic plasticity and various memory processes in rodents, including the consolidation, reconsolidation, and extinction of auditory and contextual threat memory. These findings have generated much excitement because they demonstrate the complex biochemical regulation of translation during synaptic plasticity and memory. Despite this progress, a number of critical and unresolved questions regarding the requirement for de novo protein synthesis in memory consolidation remain unanswered. We plan to focus on auditory and contextual threat memory to determine the cell types in the amygdala and hippocampus, respectively, that require eIF4E- and eIF2α-dependent translation for memory consolidation, reconsolidation, extinction, and discrimination. We also plan to examine the cell type-specific requirement for de novo translation in memory using more complex types of behavioral paradigms, including Dysregulated translation has been shown by a number of laboratories, including my laboratory, to contribute to synaptic dysfunction and aberrant behaviors in neurodegenerative diseases such as Alzheimer’s disease (AD) and neurodevelopmental disorders such as fragile X syndrome (FXS) and autism spectrum disorder (ASD). However, using molecular approaches to dissect circuit dysfunction in these diseases/disorders has been lacking. Therefore, we plan to examine the role of cell type-specific translational dysregulation in mouse models of AD, FXS, and ASD. Moreover, we will identify the inappropriately translated mRNAs and their newly synthesized protein products using translatomic and de novo proteomic approaches that we developed to identify mRNAs/proteins that are translated/synthesized improperly in mouse models of AD and FXS. These questions will be addressed by utilizing the powerful multidisciplinary combination of new groundbreaking genetically-engineered mice and viruses, electrophysiological recordings, immuno-cytochemistry, innovative methods to measure de novo protein synthesis in vivo, cell-type specific translational profiling, and de novo proteomics. The results of these studies will provide fundamental insights into the molecular events in both excitatory and inhibitory neurons that support consolidation, reconsolidation, and extinction of memory. Moreover, these studies have the potential to provide therapeutic targets for multiple brain disorders that are associated with dysregulated translation.

项目总结/摘要在过去的15年里，包括我的实验室在内的几个实验室已经确定了多种信号通路，在蛋白质合成依赖性过程中，通过翻译起始因子eIF 4 E和eIF 2 α调节翻译啮齿类动物的持久突触可塑性和各种记忆过程的形式，包括巩固，再巩固，以及听觉和背景威胁记忆的消退。这些发现产生了许多兴奋，因为它们证明了突触可塑性期间翻译的复杂生化调节和记忆尽管取得了这一进展，但仍有一些关键的未决问题，记忆巩固中的从头蛋白质合成仍然没有答案。我们计划把重点放在听觉和情境威胁记忆，以确定杏仁核和海马体中的细胞类型，分别，需要eIF 4 E和eIF 2 α依赖性翻译，用于记忆巩固、再巩固、消退，歧视我们还计划研究记忆中从头翻译的细胞类型特异性要求使用更复杂的行为模式，包括包括我的实验室在内的一些实验室已经证明，失调的翻译有助于神经退行性疾病如阿尔茨海默病（AD）中的突触功能障碍和异常行为和神经发育障碍如脆性X综合征（FXS）和自闭症谱系障碍（ASD）。然而，使用分子方法来剖析这些疾病/病症中的回路功能障碍，缺乏因此，我们计划在小鼠模型中研究细胞类型特异性翻译失调的作用 AD、FXS和ASD。此外，我们还将鉴定不适当翻译的mRNA及其新的表达。使用翻译组学和从头蛋白质组学方法合成蛋白质产物，在AD和FXS小鼠模型中不正确翻译/合成的mRNA/蛋白质。这些问题将通过利用新的突破性的强大的多学科组合来解决基因工程小鼠和病毒，电生理记录，免疫细胞化学，创新测量体内从头蛋白质合成、细胞类型特异性翻译谱和从头蛋白质合成的方法蛋白质组学这些研究的结果将提供基本的见解分子事件在这两个支持记忆巩固、再巩固和消退的兴奋性和抑制性神经元。此外，这些研究有可能为多种脑部疾病提供治疗靶点，与翻译失调有关

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

eIF2-dependent translation initiation: Memory consolidation and disruption in Alzheimer's disease.

DOI：
10.1016/j.semcdb.2021.07.009
发表时间：
2022-05
期刊：
Seminars in cell & developmental biology
影响因子：
7.3
作者：
Oliveira MM;Klann E
通讯作者：
Klann E

Spatiotemporally resolved protein synthesis as a molecular framework for memory consolidation.

DOI：
10.1016/j.tins.2022.01.004
发表时间：
2022-04
期刊：
Trends in neurosciences
影响因子：
15.9
作者：
Shrestha P;Klann E
通讯作者：
Klann E

Deletion of Fmr1 in parvalbumin-expressing neurons results in dysregulated translation and selective behavioral deficits associated with fragile X syndrome.

DOI：
10.1186/s13229-022-00509-2
发表时间：
2022-06-29
期刊：
Molecular autism
影响因子：
6.2
作者：
通讯作者：

A deep dive into local mRNA translation in neurons.

深入研究神经元中的局部 mRNA 翻译。

DOI：
10.1073/pnas.2117116118
发表时间：
2021
期刊：
Proceedings of the National Academy of Sciences of the United States of America
影响因子：
11.1
作者：
Oliveira,MauricioM;Klann,Eric
通讯作者：
Klann,Eric